2-Acyl-4-oxo-pyrazino-isoquinoline derivatives and process for the preparation thereof

ABSTRACT

2-Acyl-4-oxo-hexahydro-4H-pyrazino[2,1-a]isoquinoline derivatives of the formula ##STR1## wherein COR is the acyl radical of an up to 26 carbon atom acid and their physiologically acceptable acid addition and quaternary ammonium salts, are anthelmintics and can be produced by reacting 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline with an acid or a reactive functional derivative thereof. This is a division, or application Ser. No. 742,133, filed on Nov. 15, 1976, which in turn is a divisional of Ser. No. 533,467, filed on Dec. 16, 1974, now U.S. Pat. No. 4,001,411.

BACKGROUND OF THE INVENTION

This invention relates to novel2-acyl-4-oxohexahydro-4H-pyrazino[2,1-a]isoquinoline derivatives.

A similar compound,2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline,has been described as an intermediate in German Offenlegungsschrift No.1,470,062.

SUMMARY OF THE INVENTION

The 2-acyl-4-oxo-hexahydro-4H-pyrazino[2,1-a]isoquinoline derivatives ofthis invention are those of the general Formula 1 ##STR2## wherein CORis the acyl radical of an up to 26 carbon atom acid, with the provisothat when R is a phenyl group, the benzene ring is substituted, and thephysiologically acceptable acid addition and quaternary ammonium saltsthereof.

In a composition aspect, this invention relates to the novel compoundsof Formula 1. In another composition aspect, this invention relates topharmaceutical compositions comprising at least one such compound inadmixture with a pharmaceutically acceptable carrier. In processaspects, this invention relates to processes for the production of suchcompounds and to their use as anthelmintics.

For the sake of brevity, the following designations will be employedhereinbelow: "HPI" for the compound"4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline" and"-HPI" for the radical"-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline" lackingthe hydrogen atom on the secondary amino nitrogen atom. Accordingly, thecompounds of Formula 1 can be designaged generically as "2-acyl-HPI."

It has been found that the compounds of Formula 1 and theirphysiologically acceptable salts possess, with good compatibility,parasitological and pharmacological properties. They are effective,inter alia, as valuable anthelmintics with an especially broad spectrumof effectiveness against cestodes and trematodes. Psychotropic andblood-pressure-lowering effects can occur. The compounds of Formula 1can, therefore, be utilized as drugs in the human and/or veterinarymedicine, especially for attaining anthelmintic effects, and also asintermediates for the preparation of other medicinal agents.

Like the racemic compounds of Formula 1, the optical antipodes thereofare likewise effective, particularly those with an optical configurationcorresponding to the levorotatory HPI.

Of the 2-acyl-HPI of Formula 1, which include all those wherein the2-acyl group of any organic carboxylic acid of up to 26 carbon atomsexcept benzoic acid, preferred are those of Formulae 1a through 1j,which correspond to Formula 1 with the acyl group (--CO--R) having thefollowing values, respectively:

1a A benzoyl group substituted respectively once in the o-position byfluorine or in the m- or p-position by fluorine, chlorine, nitro,hydroxy, amino, formylamino, acetylamino, pentanoylamino, hexanoylamino,octanoylamino, oleoylamino, methoxyacetylamino, methylamino,dimethylamino, or allylamino;

1b a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orcycloheptylcarbonyl group, optionally additionally monosubstituted by,respectively, fluorine, chlorine, nitro, hydroxy, amino, formylamino,acetylamino, pentanoylamino, hexanoylamino, octanoylamino, oleoylamino,methoxyacetylamino, methylamino, dimethylamino, or allylamino;

1c an alkanoyl group of up to 8 carbon atoms optionally additionallysubstituted by methoxy or ethoxy;

1d furyl-2-carbonyl, furyl-3-carbonyl, thienyl-2-carbonyl,thienyl-3-carbonyl, or 2-thienylmercaptomethylcarbonyl;

1e a 2-, 3-, or 4-pyridylcarbonyl or 2-, 3-, or 4-N-oxidopyridylcarbonylgroup, optionally additionally monosubstituted by, respectively,fluorine, chlorine, hydroxy, amino, formylamino, acetylamino,pentanoylamino, hexanoylamino, octanoylamino, oleoylamino,methoxyacetylamino, methylamino, or dimethylamino;

1f an aminoalkanoyl group (of up to 4 carbon atoms), anaminocycloalkylcarbonyl group (of 6-8 carbon atoms), an aminobenzoylgroup, or an aminopyridylcarbonyl group substituted on the N-atom bybenzylidene, 2-hydroxybenzylidene, 2-hydroxy-3-methoxybenzylidene,carboxymethylidene, 3-phenyl-2-propenylidene, or furfurylidene;

1g a phenylazobenzoyl group, the terminal-positioned phenyl residue ofwhich in the p-position is substituted by hydroxy, alkoxy of up to 4carbon atoms, amino, alkylamino of up to 4 carbon atoms, or dialkylaminoof up to 8 carbon atoms, and which can be substituted at the otherlocations optionally additionally by carboxy, aliphatic acylamino of upto 4 carbon atoms, halogen, sulfo, or alkyl of up to 4 carbon atoms;

1h an aminocycloalkylcarbonyl group of 6-8 carbon atoms, an aminobenzoylgroup, or an aminopyridylcarbonyl group, the amino groups of which aremasked by a benzyl group optionally substituted by hydroxy and/ormethoxy;

1i a thiazolyl-, isothiazolyl-, oxazolyl-, or isoxazolylcarbonyl group,optionally additionally substituted by methyl or nitro;

1j a 2-, 3- or 4-piperidylcarbonyl group substituted on the nitrogenatom by formyl, acetyl, pentanoyl, hexanoyl, octanoyl, oleoyl,methoxyacetyl, carboxymethyl, allyl, benzyl (which can optionally besubstituted by hydroxy or methoxy), or 3-phenylpropyl, including thephysiologically acceptable acid addition and quaternary ammonium salts,and optical antipodes thereof.

Compounds of Formula 1 of particular importance are those wherein R iscyclohexyl, o-, m- and p-fluorophenyl, p-chlorophenyl, m- andp-aminophenyl, m- and p-formylaminophenyl, p-nitrophenyl and 3-pyridyl,as well as methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl,cycloheptyl, m-chlorophenyl, m- and p-hydroxyphenyl, m- andp-methylaminophenyl, m- and p-dimethylaminophenyl, m- andp-acetylaminophenyl, m- and p-methoxyacetylaminophenyl, 2-thienyl,3-thienyl, thienyl-2-mercaptomethyl, 2-furyl, 2- or 3-pyridyl,1-oxido-3-pyridinio.

In a process aspect, this invention relates to a process for thepreparation of compounds of Formula 1 which comprises:

(a) reacting4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline (HPI) witha compound of Formula 2

    R--COOH                                                    2

wherein R has the values given for Formula 1, or with a functionalderivative thereof; or

(b) cyclizing a compound of Formula 3 ##STR3## wherein R has the valuesgiven for Formula 1 and X is F, Cl, Br, I, methylsulfonyloxy orarylsulfonyloxy of 6-10 carbon atoms, preferably p-toluenesulfonyloxy,in the presence of a cyclizing agent under conditions which split offHX; or

(c) treating a compound of Formula 4 ##STR4## wherein the dashed linemeans a double bond which can be in the 6,7-position of the ring system,with a reducing agent.

Optionally, the R group of a thus-obtained compound of Formula 1thereafter is converted into another R group and/or a thus-obtainedracemic compound 1 is separated into the optical antipodes thereofand/or that a thus-obtained base of Formula 1 is converted into aphysiologically acceptable acid addition salt or a quaternary ammoniumsalt thereof or a base of Formula 1 is liberated from an acid additionsalt thereof.

It will be apparent that in the process of this invention, R can, forexample, be hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, arylor heterocyclic, and in the compounds of Formula 1, R also has thesesame values, except phenyl.

When R is alkyl, the alkyl group can be straight-chain or branched andcan contain, e.g., up to 17, preferably up to 6 carbon atoms. Cycloalkylgroups can contain, e.g., 3-12, preferably 3-7, ring carbon atoms, and alike number of total carbon atoms including those wherein 2 or 3 ringcarbon atoms form an endoalkylene bridge. Such cycloalkyl preferablycontain a total of up to 8 carbon atoms. Aralkyl groups preferablycontain up to 10 carbon atoms and the aryl group is preferably phenyl.Aryl groups can be partially or, in the case of naphthyl, completelyhydrogenated and can contain, e.g., a total of up to 10 carbon atoms and1-2 rings. Heterocyclic groups can contain, e.g., up to 10 ring atoms,up to 15 carbon atoms and 1, 2 or 3 hetero, e.g., O, N and/or S ringatoms, and can be joined directly to the carbonyl group by a ring carbonatom or indirectly through a straight-chain or branched-chain alkyl orthia-alkyl group, e.g, of up to 4 carbon atoms. Additional double and/ortriple bonds can also be contained in the alkyl, cycloalkyl,cycloalkylalkyl, aralkyl, aryl and/or heterocyclic groups. Such groupscan also be substituted by one or more conventional groups, e.g., alkyl,alkoxy, halo, nitro.

R preferably is alkyl of up to 8 carbon atoms, which can be substitutedby alkoxy of up to 4 carbon atoms; cycloalkyl of up to 7 carbon atoms,which can be substituted by fluorine, chlorine, nitro, amino, alkylaminoor dialkylamino wherein each alkyl contains up to 4 carbon atoms,allylamino, benzylamino (which can be substituted by hydroxy and/ormethoxy) or aliphatic (optionally also unsaturated) acylamino of up to18 carbon atoms, a Schiff base blocked amino group, hydroxy or alkoxy ofup to 4 carbon atoms; phenyl substituted by one or more of fluorine,chlorine, nitro, amino, alkylamino or dialkylamino of up to 4 carbonatoms in each alkyl group, allylamino, benzylamino (which can besubstituted by hydroxy and/or methoxy), aliphatic (optionally alsounsaturated) acylamino of up to 18 carbon atoms, Schiff base blockedamino, hydroxy, alkoxy of up to 4 carbon atoms, phenylazo (which can besubstituted by hydroxy, methoxy, amino, methylamino, dimethylamino,fluorine, chlorine or lower alkyl), carboxymethylamino oralkoxyacetylamino of up to 4 carbon atoms in the alkoxy group; athienyl, thienylmercaptomethyl, furyl, thiazolyl, isothiazolyl, oxazolylisoxazolyl or pyridyl group; or a piperidyl group which can besubstituted by alkyl of up to 4 carbon atoms, benzyl or aliphatic (whichcan be unsaturated) acyl of up to 18 carbon atoms.

The following are illustrative specific R values:

Alkyl, preferably of 1-6 carbon atoms, can be for example: methyl,ethyl, propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl,n-pentyl, 1-methyl-n-butyl, 2-methyl-n-butyl, isopentyl, 1-ethylpropyl,1,1-dimethyl-n-propyl, tert.-pentyl, n-hexyl, 1,1-dimethyl-n-butyl,2,2-dimethyl-n-butyl, isohexyl, n-heptyl, 1,1-dimethyl-n-pentyl,n-octyl, 2-ethylhexyl, also, n-nonyl, 1-(n-butyl)-n-pentyl, n-decyl,n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl,n-hexadecyl, n-heptadecyl and other isomers thereof, e.g., isodecyl,isododecyl.

Cycloalkyl, preferably of 3-12, more preferably 3-7 carbon atoms, canbe, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, also cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl andcyclododecyl. Two or three carbon atoms in the cycloalkyl group can bejoined together by endoalkylene bridges, for example, bridges of 1-8,preferably 1-2 carbon atoms, for example, --CH₂ -- and --CH₂ --CH₂ --,as well as --C(CH₃)₂ --, --CH₂ --CH₂ --CH₂ --CH₂ --, --C(C₂ H₅)₂ --,--CH(CH₃)--CH(CH₃)--.

Preferred cycloalkyl groups are bicyclo(2,2,1]heptyl-2,bicyclo[2,2,2]octyl-2, bicyclo[3,2,2]nonyl-2, -3 and -6. Others arebicyclo[4,2,2]decyl-2, -3 and -7, bicyclo[4,3,2]undecyl-2, -3, -7, -8and -10, or adamantyl, as well as alkylated bicyclic systems, such as,for example, 7-methylbicyclo[2,2,1]heptyl, 7-ethyl-bicyclo[2,2,1]heptyl,7,7-dimethyl-bicyclo[2,2,1]heptyl, 7,7-diethylbicyclo[2,2,1]heptyl,1,7,7-trimethyl-bicyclo[2,2,1]heptyl, 1-methylbicyclo[2,2,2]octyl, or1,2,3-trimethyl-bicyclo[2,2,2]octyl.

The cycloalkylalkyl groups preferably contain up to 8 carbon atoms andinclude, for example: cyclobutyl-methyl, cyclopentyl-methyl,cyclopentyl-ethyl, cyclohexyl-methyl and cyclohexyl-ethyl.

The alkyl and cycloalkyl groups which contain unsaturated bonds include,for example, ethenyl, ethinyl, 1-propenyl, 2-propenyl, 8-heptadecenyl,1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl,2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl,3-cycloheptenyl, 4-cycloheptenyl, as well as 1-butenyl, 2-butenyl,3-butenyl, 1-cyclooctenyl, 2-cyclooctenyl, 3-cyclooctenyl,4-cyclooctenyl, 5-cyclooctenyl, 1-propinyl and 2-propinyl.

Aralkyl preferably contains up to 10 carbon atoms, with the aryl groupbeing preferably phenyl and the alkyl group being of 1 to 4 carbon atomsincluding, for example, benzyl, 1- or 2-phenylethyl, 3-phenylpropyl,1-methyl-1-phenylethyl and 1-methyl-2-phenylethyl.

Aryl group preferably are up to 10 carbon atoms and signifies, forexample, substituted phenyl, e.g., tolyl and xylyl, naphthyl-1, ornaphthyl-2, as well as phenanthryl-1 (or -2, -3, -4, -9).

The naphthyl groups can also be partially or completely hydrogenated andinclude, for example: 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyland decalyl (cis or trans).

Heterocyclic group include, for example, heteroaromatic five- andsix-membered systems, which can be condensed optionally with one or twobenzo groups and/or a second five- or six-membered heterocyclic ring,preferred such groups including, for example: pyrryl-1 (or -2 or -3),thienyl-2 (or -3), furyl-2 (or -3), indolyl-1 (or -2, -3, -4, -5, -6 or-7), benzofuryl-2 (or -3, -4, -5, -6, or -7), benzothienyl-2 (or -3, -4,-5, -6 or -7), pyridyl-2 (or -3 or -4), α- or γ-pyranyl-2 (or -3 or -4),α- or γ-thiopyranyl-2 (or -3 or -4), quinolyl-2 (or -3, -4, -5, -6, -7,or -8), isoquinolyl-1 (or -3, -4, -5, -6, -7 or -8), as well ascarbazolyl-1 (or -2, -3, -4 or -9), pyrazolyl-1 (or -3, -4 or -5),imidazolyl-1 (or -2, -4 or -5), benzpyrazolyl-1 (or -2, -4, -5, -6 or-7), benzimidazolyl-1 (or -2, -4 or -5), oxazolyl-2 (or -4 or -5),benzoxazolyl-2 (or -4, -5, -6 or -7), thiazolyl-2 (or -4 or -5),benzthiazolyl-2 (or -4, -5, -6 or -7), isoxazolyl-3 (or -4 or -5),isothiazolyl-3 (or -4 or -5), 1,2,3-triazolyl-1 (or -2 or -4),1,2,4-triazolyl-1 (or -3 or -5), tetrazolyl-1 (or -2 or -5), 1,2,3- or1,2,4-oxadiazolyl, 1,2,4-, 1,3,4- or 2,1,5-thiadiazolyl,2,1,3-benzothiadiazolyl-5, acridinyl-1 (or -2, -3, -4, -5, -6, -7, -8 or-9), pyridazinyl-3 (or -4), pyrimidinyl-2 (or -4 or -5), pyrazinyl,phenazinyl-1 (or -2), phenoxazinyl-1 (or -2, -3, -4 or -9),phenothiazinyl-1 (or -2, -3, -4 or -9), thianthrenyl-1 (or -2), 1,2,5-,1,2,4- or 1,2,3-triazinyl, 1,2,3,4- or 1,2,4,5-tetrazinyl, purinyl-2 (or-6, -7, -8 or -9), pyrazolo[3,4-d]pyrimidinyl-2 (or -6, -7 or -9),pteridinyl, cinnolinyl-3 (or -4, -5, -6, -7 or -8), phthalazinyl-1 (or-5 or -6), quinazolinyl-2 (or -4, -5, -6, -7 or -8), quinoxalinyl-2 (or-5 or -6), 1,5-naphthyridinyl-2 (or -3 or -4) or nalidixinyl. Theheterocyclic groups can also be partially or completely hydrogenated andpreferably are 1,4-dioxanyl, morpholinyl, pyrrolidinyl, tetrahydrofuryl,tetrahydrothienyl, pyrazolidinyl, imidazolidinyl,1,2,3,4-tetrahydropyridyl, 1,2,5,6-tetrahydropyridyl, piperidyl,tetrahydropyranyl, 1,2,3,4-tetrahydroquinolyl,1,2,3,4-tetrahydroisoquinolyl, hexahydropyridazinyl,hexahydropyrimidinyl or piperazinyl; as well as 1,3-dioxanyl,pyrrolinyl, dihydrofuryl, pyrazolinyl, imidazolinyl, oxazolinyl,oxazolidinyl, thiazolinyl, thiazolidinyl, isoxazolidinyl,isothiazolinyl, isothiazolidinyl, 2,3-dihydrobenzthiazolyl,1,2-dihydroquinolyl, 3,4-dihydroquinolyl, 1,2-dihydroisoquinolyl,3,4-dihydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl,chromenyl, chromanyl, dihydropyridazinyl, tetrahydropyridazinyl,dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrazinyl,tetrahydropyrazinyl or 1,4-thiazinyl.

These alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, andheterocyclic groups optionally can be mono- and polysubstituted,including those having several substituents on one carbon atom,including substituents in the cis- or trans-position. Suitablesubstituents are, for example, one or more of:

Alkyl of up to 4 carbon atoms, preferably methyl or ethyl, as well asn-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl;haloalkyl of up to 4 carbon atoms, for example, fluoromethyl,trifluoromethyl or chloromethyl; hydroxyalkyl of up to 4 carbon atoms,e.g., hydroxymethyl or hydroxyethyl, aminoalkyl of up to 4 carbon atoms,and corresponding mono- and dimethyl- as well as mono- and diethylaminogroups, preferably aminomethyl, methylaminomethyl, dimethylaminomethyl,methylaminoethyl, dimethylaminoethyl, as well as ethylaminomethyl,diethylaminomethyl, ethylaminoethyl, diethylaminoethyl,methylamino-n-propyl, dimethylamino-n-propyl, diethylamino-n-butyl,etc.; aryl of 6-10 carbon atoms, preferably phenyl; aralkyl of 7-19carbon atoms, preferably benzyl, as well as triphenylmethyl; halogen,preferably fluorine or chlorine, as well as bromine and iodine; hydroxy;alkoxy of up to 4 carbon atoms, preferably methoxy or ethoxy, as well asn-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy or tert.-butoxy;acyloxy of up to 4 carbon atoms, e.g., formyloxy, acetoxy orpropionyloxy; substituted acetoxy, e.g., trifluoroacetoxy ormethoxyacetoxy; aryloxy of 6-10 carbon atoms, preferably phenoxy;substituted aryloxy, e.g., o-, m- or p-fluorophenoxy, o-, m- orp-chlorophenoxy, o-, m- or p-aminophenoxy, o-, m- orp-methylaminophenoxy, o-, m- or p-dimethylaminophenoxy, o-, m- orp-formylaminophenoxy or o-, m- or p-acetylaminophenoxy; amino;alkylamino of up to 4 carbon atoms, preferably methylamino, ethylamino,as well as n-propylamino, isopropylamino, n-butylamino, isobutylamino.,sec.-butylamino or tert.-butylamino; dialkylamino with alkyl groups eachof up to 4 carbon atoms, preferably dimethylamino, diethylamino, ormethylethylamino, as well as methyl-n-propylamino, methylisopropylamino,methyl-n-butylamino, ethyl-n-propylamino, ethylisopropylamino,ethyl-n-butylamino, di-n-propylamino, diisopropylamino ordi-n-butylamino; trialkylammonium with alkyl groups each of up to 4carbon atoms, e.g., trimethylammonium, triethylammonium; alkenylamino ofup to 4 carbon atoms, e.g., vinylamino, 1-propenylamino, allylamino,1-butenylamino, 2-butenylamino or 3-butenylamino; aralkyl optionallysubstituted by OH, OCH₃, NHCH₃, N(CH₃)₂, SCH₃, CH₃ and/or C₂ H₅, forexample, benzylamino, 2-hydroxybenzylamino,2-hydroxy-3-methoxybenzylamino; acylamino of up to 18 carbon atoms,wherein acyl is that of a saturated or unsaturated fatty acid,preferably a fatty acid of 1-18 carbon atoms, e.g., formylamino,acetylamino, propionylamino, butyrylamino, pentanoylamino,hexanoylamino, heptanoylamino, octanoylamino, decanoylamino,dodecanoylamino, palmitoylamino, stearoylamino, oleoylamino,linoloylamino, linolenoylamino; acylamino wherein the acyl radical isthat of trifluoroacetic acid or a lower-alkoxyacetic acid (alkoxy of 1-4carbon atoms), e.g., trifluoroacetylamino, methoxyacetylamino,ethoxyacetylamino, propoxyacetylamino, isopropoxyacetylamino,butoxyacetylamino, tert.-butoxyacetylamino; acylamino wherein acyl isthe acyl radical of a dicarboxylic acid (of 4-8 carbon atoms) which canform cyclic anhydrides, for example, 3-carboxypropionylamino(succinoylamino), 3-carboxy-cis-prop-2-enylamino (maleinoylamino),2-carboxycyclopentylcarbonylamino, 2-carboxycyclohexylcarbonylamino,phthaloylamino, 2- or 3-carboxypyridyl-3- or -2-carbonylamino,3-(carboxyethylmercapto)-propionylamino; sulfamino; hydroxycarbonylaminosubstituted by an organic radical of up to 15 carbon atoms, e.g.,ethoxycarbonylamino, tert.-butoxycarbonylamino, benzyloxycarbonylaminoor 3,5-dimethoxybenzyloxycarbonylamino, as well ascyano-tert.-butoxycarbonylamino,2-biphenylyl-(4)-isopropoxycarbonylamino,2,2,2-trichloroethoxycarbonylamino, fluorenyl-(9)-methoxycarbonylamino,p-nitrobenzyloxycarbonylamino, p-chlorobenzyloxycarbonylamino,p-phenylazobenzyloxycarbonylamino,p-(p-methoxyphenylazo)benzyloxycarbonylamino andcyclopentyloxycarbonylamino; alkylidene- or aralkylideneamino of up to 9carbon atoms, such as, e.g., benzylideneamino, p-methylbenzylideneamino,o-hydroxybenzylideneamino, p-methoxybenzylideneamino,3,4-dimethoxybenzylideneamino, 2-hydroxy-3-methoxybenzylideneamino,isopropylideneamino, sec.-butylideneamino, carboxymethyleneamino,3-phenyl-2-propen-1-ylideneamino, furfurylideneamino and5-nitrofurfurylideneamino; sulfo and disulfo groups formed by theaddition of bisulfite to the last-mentioned groups, e.g.,α-sulfobenzylamino, α-sulfo-2-hydroxybenzylamino,α-sulfo-2-hydroxy-3-methoxybenzylamino, sulfomethylamino,1-sulfoethylamino, 1-sulfo-1-carboxymethylamino,(1,3-disulfo-3-phenyl)-propylamino; phenylazo (preferably p-substituted)or naphthylazo-1 or -2 substituted by hydroxy, alkoxy of up to 4 carbonatoms (e.g., methoxy or ethoxy), amino, alkylamino of up to 4 carbonatoms (e.g., methylamino or ethylamino) and/or dialkylamino of up to 8carbon atoms, (e.g., dimethylamino or diethylamino), which three groupscan optionally also be substituted by carboxy, lower alkoxycarbonyl(e.g., methoxycarbonyl and ethoxycarbonyl), acylamino of up to 4 carbonatoms (e.g., formylamino and acetylamino), halogen (e.g., fluorine,chlorine and bromine), sulfo, alkoxysulfonyl (e.g., methoxysulfonyl andethoxysulfonyl) and/or alkyl of up to 4 carbon atoms (e.g., methyl,ethyl, propyl, isobutyl, tert.-butyl); for example,3-carboxy-4-hydroxyphenylazo, 4-dimethylaminophenylazo,4-diethylaminophenylazo, 2-methyl-4-hydroxyphenylazo, 4-methoxy- or4-ethoxyphenylazo; an amino group blocked by a mono- or disaccharideradical containing 5-12 carbon atoms, preferably a monosaccharide whosehydroxy group on the number 1 carbon atom and/or on the end-positionedcarbon atom oxidized to the carboxylic acid, preferably gluconoylamino,glucuronoylamino, saccharoylamino, galactonoylamino, galacturonoylamino,mucoylamino, mannonoylamino, manno-saccharoylamino, arabinonoylamino andribonoylamino, as well as maltobionoylamino, lactobionoylamino andsaccharobionoylamino; mercapto; alkylmercapto of up to 4 carbon atoms,preferably methylmercapto and ethylmercapto, as well asn-propylmercapto, isopropylmercapto, n-butylmercapto, isobutylmercapto,sec.-butylmercapto and tert.-butylmercapto; arylmercapto of 6-10 carbonatoms, preferably phenylmercapto; acylmercapto of up to 4 carbon atoms,e.g., formylmercapto, acetylmercapto and propionylmercapto;thienyl-2-mercapto; and thienyl-3-mercapto; nitro; cyano; carboxy,alkoxycarbonyl of up to 4 carbon atoms in the alkoxy group preferablymethoxycarbonyl and ethoxycarbonyl, as well as n-propoxycarbonyl,isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl,sec.-butoxycarbonyl, or tert.-butoxycarbonyl; hydrazino; alkyl- orarylhydrazino, such as 1-methylhydrazino, 2-methylhydrazino,1-ethylhydrazino, 2-ethylhydrazino, 1,2-dimethylhydrazino,2,2-dimethylhyrazino, 1,2,2-trimethylhydrazino and 2-phenylhydrazino;azido; sulfo, alkoxy sulfonyl or aryloxysulfonyl of up to 7 carbonatoms, such as, for example, methoxysulfonyl, ethoxysulfonyl, orp-tolyloxysulfonyl; sulfur (as the thione group) and/or oxygen,preferably as the keto or N-oxido group (N-oxide).

If secondary amino groups are present in the R-group, these can besubstituted by various acyl groups, for example, by an optionallyunsaturated aliphatic acyl group of 1-18 carbon atoms, e.g., formyl,acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl,octanoyl, nonanoyl, decanoyl, dodecanoyl, palmitoyl, stearoyl, oleoyl,linoloyl, linolenoyl; or by an alkoxyacetyl group of 1-4 carbon atoms inthe alkoxy group, e.g., methoxyacetyl, ethoxyacetyl, propoxyacetyl,butoxyacetyl, isobutoxyacetyl, tert.-butoxyacetyl; or by a mono- ordisaccharide group oxidized to the carboxylic acid on the number 1carbon atom and/or on the terminal-positioned carbon atom, e.g.,gluconoyl, glucuronoyl, saccharoyl, galactonoyl, galacturonoyl, mucoyl,mannonoyl, mannosaccharoyl, arabinonoyl, ribonoyl, maltobionoyl,lactobionoyl, saccharobionoyl; or by the acyl group of a dicarboxylicacid (of 4-8 carbon atoms) which can form cyclic anhydrides, e.g.,3-carboxypropionyl (succinoyl), 3-carboxy-cis-prop-2-enoyl (maleinoyl),2-carboxycyclohexylcarbonyl, phthaloyl, 2- or 3-carboxypyridyl-3- or-2-carbonyl, 3-(carboxyethylmercapto)-propionyl; or by a sulfone group.

If carboxy or sulfo groups are present in the R group, these can also bepresent in the form of their alkali metal, alkaline earth metal orammonium salts, preferably in the form of their sodium or potassiumsalts.

The starting materials of Formula 2 can be utilized in the form of thefree acids or as functional derivatives thereof. Suitable functionalderivatives are, for example, alkyl esters, lactones, halogenides,azides, as well as anhydrides. The alkyl groups of the esters cancontain up to 4 carbon atoms and can be, for example, methyl, ethyl,propyl, isopropyl, n-butyl, isobutyl, and tert.-butyl. Suitable lactonesare, e.g., 4-butyrolactone, as well as 4- and 5-valerolactone, as wellas 3-hydroxy-3-methyl-5-valerolactone. Preferred halogenides are thechlorides or bromides, as well as the fluorides or iodides. Suitableanhydrides are, in addition to the symmetrical anhydrides, also mixed,cyclic, and Leuchs anhydrides, insofar as these can be formed. Preferredacyloxy groups in the mixed anhydrides (compounds 2 wherein the OH-groupis substituted by acyloxy) are the trifluoroacetoxy, acetoxy andformyloxy groups, as well as propionyloxy, butyryloxy, isobutyryloxy.Cyclic anhydrides can be derived from dicarboxylic acids, for example,from glutaric acid, maleic acid, succinic acid,cyclobutane-1,2-dicarboxylic acid, cyclopentane-1,2-dicarboxylic acid,cyclohexane-1,2-dicarboxylic acid, phthalic acid. Leuchs anhydrides areformed, for example, from amino acids and phosgene, e.g., from the1-amino-1-carboxylic acids of cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane or thiopyran, as well as from aliphatic aminoacids, such as glycine, leucine and isoleucine.

Of the groups wherein X is arylsulfonyloxy, preferred arephenylsulfonyloxy and p-tolylsulfonyloxy, as well as, for example,naphthyl-1-sulfonyloxy or naphthyl-2-sulfonyloxy.

The preparation of the compounds of Formula 1 and also the conversion ofthus-produced compounds of Formula 1 into other compounds of Formula 1takes place otherwise in accordance with methods known from theliterature (described, for example, in the standard works such asHouben-Weyl, "Methoden der Organischen Chemis," [Methods of OrganicChemistry], Georg-Thieme publishers, Stuttgart), namely under thereaction conditions known and suitable for the individual reactions.

All starting materials for the preparation of the compounds of Formula 1can, if desired, also be formed in situ so that they are not isolatedfrom the reaction mixture but rather are immediately further reacted tocompounds 1.

The compounds 1 can preferably be produced by reacting HPI with acarboxylic acid 2 or one of the functional derivatives thereof.Preferred functional derivatives are the carboxylic acid anhydrides,also mixed carboxylic acid anhydrides, e.g., the p-fluorobenzoicacid-formic acid anhydride, the carboxylic acid halogenides (e.g., thefluoride, chloride, bromide, iodide), or the azides. An excess of thecarboxylic acid derivative can be used as the solvent, or an inertsolvent is used, for example, aromatic hydrocarbons, such as benzene ortoluene; ethers, such as diisopropyl ether, tetrahydrofuran (THF), ordioxane; nitriles, such as acetonitrile; or halogenated hydrocarbons,such as dichloromethane, chloroform, carbon tetrachloride, orchlorobenzene. During the acylation, an inorganic or organic base ispreferably added, e.g., sodium hydroxide, potassium hydroxide, sodium orpotassium carbonate, pyridine, triethylamine, triisopropylamine. Thereaction with the acid 2 itself is conducted between about 0° and 200°;when using the functional derivatives of the acid, the reaction iscarried out between about 0° and the boiling point of the solvent used,preferably between about 0° and 80°. The reaction times range betweenabout 10 minutes and 48 hours, preferably between 30 minutes and 5hours.

It is also possible to produce the carboxylic acid halogenides,especially the chlorides, in situ, for example from the carboxylic acidsof Formula 2 and halogenating reagents, e.g., silicon tetrachloride,phosphorus trichloride or -bromide phosphorus oxychloride, thionylchloride, or phosphorus pentachloride, suitably in one of theaforementioned solvents and/or with the addition of one of theabove-mentioned organic bases. Temperatures of 40°-200°, especially70°-140°, are preferred.

The reaction of HPI with a free carboxylic acid 2 can be accomplished,for example, in the presence of dicyclohexylcarbodiimide in one of theaforementioned inert solvents or in pyridine. Low temperatures (e.g.,0°-20°) are preferred for this reaction.

It is also possible to react the HPI with one of the above-mentionedlactones, suitably in the presence or absence of a basic catalyst, suchas sodium or potassium hydride, usually in the presence of an inertsolvent, such as xylene, dimethylformamide (DMF), dimethyl sulfoxide,sulfolane, dioxane, THF, or diethyl ether at temperatures of betweenabout 0° and about 200°.

In addition to the racemic HPI, one of its two optical antipodes canalso serve as the starting material. Preferably, the (-)-antipode isused, which can be converted, by acylation, into pharmacologicallyparticularly valuable, optically active compounds 1.

The starting compounds (HPI as well as the carboxylic acids of Formula2) are known or can be prepared analogously to conventional compoundsaccording to standard methods.

It is also possible to obtain compounds of Formula 1 by cyclizing acompound of Formula 3 in the presence of a cyclizing agent underconditions wherein HX is split off. Suitable cyclizing media are strongbases, such as preferably butyllithium or potassium tert.-butylate,further phenyllithium, sodium hydride, alcoholates such as sodium orpotassium methylate, ethylate, propylate, isopropylate, n-butylate,tert.-butylate, amides such as lithium diisopropylamide or thecorresponding sodium or potassium amide. Normally, the reaction iscarried out in inert solvents, such as benzene, hexane, tert.-butanolTHF, hexamethylphosphoric triamide, dioxane, ether, DMF, dimethylsulfoxide, acetonitrile, optionally under nitrogen. The reactiontemperatures range between about -20° and the boiling point of thesolvent used. The reaction takes between about 15 minutes and about 30hours, preferably 10-14 hours.

The cyclization can also be effected with optically active compounds ofFormula 3, which leads to optically active compounds 1.

The starting compounds of Formula 3 are accessible according to methodsknown from the literature, for example from the corresponding1-cyano-1,2-dihydro- or 1-cyano-1,2,3,4-tetrahydroisoquinolinessubstituted in the 2-position by the residue R--CO-- (having the valuesgiven for Formula 1). These compounds are hydrogenated on Raney nickelat elevated temperatures and pressures, the R--CO group migrating, tothe corresponding N-(1,2,3,4-tetrahydroisoquinolyl-1-methyl)-acylamideswhich can then be converted, with compounds of the formula X--CH₂--CO--X, e.g., chloracetyl chloride, into the compounds 3.

It is furthermore possible to produce the compounds of Formula 1 by thereduction, preferably the catalytic hydrogenation, of a compound ofFormula 4. Suitable catalysts are those known from the literature inthis connection, preferably noble metal catalysts, but alsocopper-chromium oxide, as well as nickel and cobalt catalysts. The noblemetal catalysts can be used, for example, as supported catalysts (e.g.,palladium on charcoal), as oxide catalysts (e.g., platinum oxide), or asfinely divided metallic catalysts (e.g., platinum black). Nickel andcobalt catalysts are suitably employed as the Raney metals, and nickelis utilized also on kieselguhr or pumice as the support. Thehydrogenation can be conducted under pressures of between about 1 and200 atmospheres and temperatures of between about 0° and 200°,advantageously in the presence of a solvent, preferably an alcohol, suchas methanol, ethanol, isopropanol, or tert.-butanol; ethyl acetate; anether such as dioxane or THF; water; and/or an alkaline solution. Ifdesired, the hydrogenation can also be effected in a homogeneous phase.Suitable catalysts for this purpose are, for example, complex compoundsof heavy metals, e.g., soluble rhodium complexes, such as rhodiumhydridocarbonyl-tris(triphenylphosphine).

The reduction of compounds 4 can also be controlled so that solely oneantipode of compounds 1 is produced, or is obtained to a predominantextent. This can be done, for example, by asymmetrical hydrogenation. Asuitable catalyst for this reaction is Raney nickel, for example, whichhad previously been treated with asymmetrically modifying reagents,e.g., with aqueous solutions of optically active hydroxy or amino acids,such as tartaric acid, citric acid, alanine, isoleucine, lysine,phenylalanine, valine, or leucine.

Furthermore, heavy metal catalysts applied to natural or syntheticpolymers can be utilized for an asymmetrical hydrogenation, for examplepalladium or platinum on silk or on specially prepared silica gel orpolyamino acid supports as described in the literature. In thehomogeneous phase, an asymmetrical hydrogenation is accomplished, forexample, on optically active soluble rhodium complexes. The asymmetricalhydrogenation is effected under the above-indicated conditions,preferably at 1-3 atmospheres and temperatures of between 20° and 50°.

The starting compounds 4 can be prepared, for example, bydehydrogenating a corresponding compound of Formula 1, saturated in the11b(1)-position, with sulfur, selenium, chloranil, or anotherdehydrogenating agent known from the literature. Such a reaction is ofinterest, in particular, if the compound saturated in the11b(2)-position is present as an optically active antipode and is lesseffective than the other possible antipode. In this case, the lessereffective antipode can be converted, by dehydrogenation, into compound4, and the latter can be converted, by subsequent hydrogenation, intothe more effective saturated racemate of Formula 1 or, by asymmetricalhydrogenation, primarily into the more effective antipode of Formula 1.

In a thus-obtained compound of Formula 1, the R group can optionally beconverted into another R group according to methods disclosed in theliterature. For example, already present substituents can be convertedinto other substituents.

Thus, it is possible to reduce a reducible substituent, such as thenitro group, suitably by catalytic hydrogenation or also by chemicalmethods. The catalytic hydrogenation can be conducted according to theabove-mentioned conditions. Suitable for reducing purposes are alsometals (e.g., iron, zinc) with acids (e.g., HCl, CH₃ COOH) or tin(II)chloride.

An additional keto group in the acyl residue of compound 1 can beconverted into a hydroxy group by hydrogenation or by chemical reaction.The above-mentioned methods are preferred for conducting thehydrogenation. Furthermore, the keto group can be reduced with nascenthydrogen, e.g., by treatment with zinc/acid or zinc/alkaline solution; asuitable acid, for example, is acetic acid. Also sodium or anotheralkali metal can be used in a lower alcohol (such as ethanol,isopropanol, isoamyl alcohol). The keto group can also be reduced withmetallic hydrides. Preferred are complex metallic hydrides which do notattack the amide group of the ring system, such as sodium borohydride,lithium borohydride, potassium tri-(sec.-butyl)-borohydride, potassiumtrimethoxyborohydride, suitably in the presence of an inert solvent,such as an ether, e.g., diethyl ether, THF, dioxane,1,2-dimethoxyethane, or diglyme. Sodium borohydride can also be used inan aqueous or aqueous-alcoholic solution. The reaction takes placebetween about -80° and +100°, especially between -20° and the boilingpoint of the solvent utilized.

Furthermore, a keto group can be converted into a methylene group byreaction with hydrazine and subsequent decomposition of the thus-formedhydrazone according to the method by Wolff-Kishner. Also, it is possibleaccording to the abovementioned conditions to hydrogenate double bondsto single bonds and triple bonds to double or single bonds. With the aidof hydrogen/palladium, it is also possible to reduce an N-oxide group inthe R group to the corresponding tertiary amine in accordance with knownmethods.

A thus-obtained compound 1 which contains a tertiary nitrogen atom inthe acyl residue can be converted into the corresponding N-oxide byreaction with inorganic or organic peroxides, e.g., hydrogen peroxide(preferably a 30% aqueous solution or mixtures of hydrogen peroxide withformic acid), peracetic acid, perbenzoic acid, 3-chloroperbenzoic acid,or tert.-butylhydroperoxide. Suitable solvents for the organic peroxidesare, for example, methylene chloride, chloroform, or alcohols such asmethanol or isopropanol. The reaction is conducted at temperatures ofbetween about 0° and 50°, preferably at room temperature. The reactiontimes range between about 1 and 48 hours.

Thus-obtained compound 1 carrying a mercapto group in the R group can beoxidized to the corresponding sulfo compounds for example with nitricacid. Analogously, corresponding alkylmercapto compounds can beconverted into sulfoxides or sulfones, for example with nitric acid,aqueous solutions of hydrogen peroxide, or 3-chloroperbenzoic acid.

Alcohol groups in the R group can be converted into carbonyl groups, forexample by oxidation with manganese dioxide or chromic acid.

Compounds 1 containing one or more free hydroxy, mercapto, amino, ormonoalkylamino groups as substituents can be alkylated to thecorresponding alkoxy, alkylmercapto, monoalkylamino, dialkylamino, ortrialkylammonium compounds, or they can be acylated to the correspondingacyl compounds.

For the O- and S-alkylation, the starting compounds are suitably firstconverted into the corresponding salts by the addition of a base, e.g.,sodium hydroxide solution, potassium hydroxide, or potassium carbonate.Suitable alkylating agents are, for example, alkyl halogenides, such asmethyl chloride, bromide, or iodide, ethyl chloride, bromide, or iodide,the corresponding dialkylsulfuric acid esters or the alkylsulfonic acidesters, e.g., dimethyl sulfate, diethyl sulfate, or methylp-toluenesulfonate, or diazo compounds, such as diazomethane. Aminocompounds can also be reductively alkylated with formaldehyde oracetaldehyde in the presence of hydrogen on a catalyst or in thepresence of formic acid. Suitable solvents are, for example, water;aqueous sodium hydroxide solution; alcohols, such as methanol, ethanol,or n-butanol; hydrocarbons, such as benzene or xylene; ethers, such asTHF or dioxane; amides, such as DMF. The alkylations take place suitablyat temperatures between about -10° and about +150°, especially betweenroom temperature and boiling temperature of the solvent employed.

A corresponding acylation takes place suitably with carboxylic acids orcarboxylic acid derivatives, for example under the conditions indicatedabove for the acylation of HPI. An acylation can also be accomplishedwith ketenes, preferably in inert solvents, such as ether,dichloromethane, chloroform, benzene, or toluene, optionally with theaddition of acidic catalysts, such as sulfuric acid or p-toluenesulfonicacid. Thus, it is possible, for example, to obtain from2-(4-hydroxybenzoyl)-HPI and ketene the final product2-(4-acetoxybenzoyl)-HPI.

By reacting thus-obtained compounds of Formula 1 which contain a primaryor secondary amino group in the R group with a derivative of a saccharicacid under the above-mentioned conditions, compounds can be preparedwherein the amino group in the R group is masked by a saccharic acidgroup. Suitable saccharic acid R groups are, for example, the lactonesof the sugars, such as gluconic acid lactone or glucuronic acid lactone.

It is also possible to react amino groups in the R group with asaccharic acid (or a functional derivative thereof) masked on theremaining OH-groups (for example by benzyl groups), and then split offthe masking groups (for example by hydrogenation). Thus,2-(4-gluconoylaminobenzoyl)-HPI can be produced, for example, byreaction of 2-(4-aminobenzyl)-HPI with2,3,4,5,6-penta-O-benzyl-gluconoyl chloride and subsequenthydrogenolysis of the benzyl groups in the thus-obtained2-[4-(2,3,4,5,6,-penta-O-benzyl-gluconoylamino)-benzoyl]-HPI.

Compounds 1, the amino group or groups of which is (are) masked in the Rgroup by one (or several) sulfo group(s), can be obtained fromthus-produced compounds 1 with one (or several) free amino group(s) inthe R group by reaction with chlorosulfonic acid, for example under theconditions disclosed above for the reaction of HPI with acidhalogenides.

It is also possible to convert acyloxy (e.g., formyloxy, acetoxy,trifluoroacetoxy, phthaloyloxy, or other readily saponifiable acyloxygroups), acylmercapto, or alkoxycarbonyl (e.g., methoxycarbonyl orethoxycarbonyl) groups in thus-obtained compounds in Formula 1 bytreatment with solvolyzing agents into hydroxy, mercapto, or carboxygroups. For this purpose, acids are utilized (such as hydrochloric acidor acetic acid), or preferably bases are employed, such as sodium orpotassium carbonate, calcium, barium, sodium, or potassium hydroxide,for example in aqueous methanol. Gentle reaction conditions arepreferred so that the acid amide groups are not attacked. In general,the reaction is accomplished at temperatures of between about -40° and+90° and in a period of 2-50 hours.

Cyano groups in compounds 1 can be hydrolyzed to carbamoyl groups in anacidic medium (e.g., with HCl or H₂ SO₄ in water, methanol, ethanol,aqueous dioxane, or acetic acid) or in an alkaline medium (e.g., withKOH in aqueous ethanol or in cyclohexanol). It is also possible toconduct the reaction with H₂ O₂ in an alkaline solution, generally attemperatures of between room temperature and 80° during a period of 1-5hours.

Compounds 1 wherein an amino group in the acyl group is masked in theform of a Schiff base can be converted into the corresponding secondaryamines by hydrogenolysis. The Schiff bases are preferably derived fromaldehydes, such as formaldehyde, benzaldehyde, or glyoxylic acid, andalso from ketones, such as acetone. For the hydrogenation, hydrogen isused, for example, in the presence of platinum or Raney nickel at roomtemperature and under normal pressure.

Benzylamino compounds can be split into the corresponding primaryamines, for example, with hydrogen in the presence of a noble metalcatalyst, such as palladium.

It is also possible to convert thus-produced Schiff bases by reactionwith bisulfite into the corresponding bisulfite adducts. The bisulfiteadducts can also be obtained by the direct reaction of analdehyde-bisulfite addition product with a compound 1 which carries afree amino group in the R group.

Urethane group, e.g., N-ethoxycarbonyl or N-benzyloxycarbonyl groups, inthe R group of compounds 1 can be split, for example with hydrogenchloride in acetic acid.

From thiourethane groups present in the R group of compounds 1, thecorresponding amino groups can be liberated with alkali metal acetate orlead(II) acetate in alcohols, such as methanol or ethanol, or withalkali metal hydroxide solution in the presence of lead(II) hydroxide orlead(II) carbonate.

Quite basically, suitable masking groups for an amino group in the acylresidue of compounds 1 are all those successfully employed in peptidesyntheses. Correspondingly, methods known from the literature can alsobe used to split off these masking groups.

It is further possible to convert an alkylamino substituent in compounds1 into a 1-alkylhydrazino substituent, for example by reaction withnitrous acid and reduction of the thus-produced nitrosamine with nascenthydrogen (e.g., from zinc/acetic acid) or with tin(II) chloride.

Furthermore, keto groups in the R group of compounds 1 can be convertedinto amino groups. For example, the ketones can be reacted withhydroxylamine or with hydrazine, and the thus-produced oximes orhydrazones can be hydrogenated, for example, on Raney nickel at about1-50 atmospheres. According to another mode of operation, ketones can behydrogenated in the presence of ammonia or primary or secondary amines.In this case, primary, secondary, or tertiary amines 1 are obtained. Thereaction proceeds preferably under pressures of between 1 and 200atmospheres and at temperatures of between -40° and 150° in methanol,ethanol, isopropanol, THF, dioxane, or liquid ammonia, for example.

Furthermore, keto groups in compounds 1 can be converted according tocustomary methods into CF₂ -groups, for example with sulfurtetrafluoride or phenylsulfur trifluoride in the presence ofhydrofluoric acid or also with carbonyl difluoride in the presence ofpyridine. The reaction is preferably conducted in an autoclave underslight excess pressure in inert solvents, such as methylene chloride,chloroform, or THF at temperatures of between 0° and 150°.

It is also possible to split alkoxy or alkylmercapto groups present inthus-obtained compounds 1, thus producing hydroxy or mercapto groups. Inthis reaction, conditions must be selected under which the acid amidegroupings remain preserved. Suitably, a Lewis acid is utilized, such asboron tribromide, in an inert solvent, such as dichloromethane,chloroform, or carbon tetrachloride at temperatures of between about-40° and +50°.

Compounds 1 containing one or more amino groups can be converted intothe corresponding diazonium compounds in accordance with conventionalmethods by diazotization; in these diazonium compounds, the diazoniumgroup can be exchanged, for example, against fluorine, chlorine,bromine, iodine, cyano, OH, SH, O-alkyl, or S-alkyl. The diazotizationof the corresponding amino compounds can be effected, for example, in asulfuric acid, hydrochloric acid, hydrobromic acid and/or tetrafluoboricacid aqueous solution by adding an inorganic nitrite, preferably NaNO₂or KNO₂, at temperatures of between about -20° and +10°. It is alsopossible to conduct the reaction with an organic nitrite, such asn-butyl nitrite, n-amyl nitrite, or isoamyl nitrite, at temperatures ofbetween -20° and +5° in inert organic solvents, such as diethyl ether,THF, or dioxane.

To introduce a fluorine atom, the diazotization is conducted, forexample, in anhydrous hydrofluoric acid, thereafter heating the reactionmixture; alternatively, the diazonium salts are reacted with HBF₄ to thesparingly soluble diazonium tetrafluoborates. The latter can be isolatedand converted by a heat treatment, e.g., by heating in an inert solvent,to the desired fluorine compounds. The diazonium tetrafluoborates(especially those of heterocyclic compounds) can, however, also beirradiated, without isolation, in an aqueous suspension with a mercurylamp, thus yielding the desired fluorine compounds. The diazonium groupcan be exchanged against chlorine or bromine preferably in a hot aqueoussolution in the presence of Cu₂ Cl₂ or Cu₂ Br₂. The exchange of adiazonium iodide group against iodine is accomplished already by slightheating, and in this reaction Cu₂ I₂, Cu₂ Br₂, or Cu₂ Cl₂ can be addedto the mixture. A replacement of the diazonium group by CN isaccomplished, for example, in the presence of Cu₂ (CN)₂ and alkali metalcyanides (such as NaCN, KCN) at about 0° to +5° . The diazonium saltgrouping can also be exchanged against an alkoxy group, for example byheating in an aqueous-alcoholic solution. An exchange against a mercaptogroup takes place suitably by reacting the diazonium compound with analkali metal xanthate, e.g. with sodium ethyl xanthate, and subsequentalkaline saponification.

The diazonium compounds can also be coupled, with the use of suitablecouplers, to the corresponding azo dyes. Primarily feasible couplers arebenzene derivatives carrying activating substituents, such as amino,alkylamino, dialkylamino, hydroxy, or alkoxy groups and which canfurthermore contain additional substituents, such as carboxy, halogen(preferably fluorine or chlorine), sulfo, or alkyl groups.

Basic compounds 1 can optionally be converted into the physiologicallyacceptable acid addition salts thereof. Suitable for this purpose areinorganic or organic, e.g. aliphatic, alicyclic, araliphatic, aromatic,or heterocyclic mono- or polybasic carboxylic or sulfonic acids, e.g.mineral acids, such as hydrochloric, hydrobromic, or hydriodic acid,sulfuric acid, nitric acid, phosphoric acids, such as orthophosphoricacid, sulfamic acid; organic acids, such as formic, acetic, propionic,butyric, pivalic, diethylacetic, oxalic, malonic, succinic, pimelic,fumaric, maleic, citric, gluconic, lactic, tartaric, malic, benzoic,salicylic, phenylpropionic, ascorbic, isonicotinic, methanesulfonic,ethanedisulfonic, 2-hydroxyethanesulfonic (isethionic),p-toluenesulfonic, naphthalenemono- or -disulfonic acids (for examplenaphthalene-1-or -2-sulfonic or naphthalene-1,5- or 2,6-disulfonicacid).

Compounds 1 with a free carboxyl or sulfo group can be converted intoone of their physiologically acceptable metal or ammonium salts byreaction with a base. Especially suitable salts are the sodium,potassium, magnesium, calcium, and ammonium salts, furthermoresubstituted ammonium salts, such as, for example, the dimethyl- anddiethylammonium, cyclohexylammonium, dicyclohexylammonium, N-alkyl- orN-aryl-substituted piperazinium salts (such as the methylpiperazinium orethylpiperazinium salts), as well as the N,N-dibenzylethylenediammoniumsalts.

Conversely, basic compounds 1 can be liberated from the acid additionsalts thereof by treatment with bases, such as sodium or potassiumhydroxide, sodium or potassium carbonate, and acidic compounds 1 can beliberated from their metallic and ammonium salts by treatment withacids, especially mineral acids, such as dilute hydrochloric or sulfuricacid.

Compounds 1 carrying a primary, secondary, or tertiary amino group canbe converted into the physiologically acceptable quaternary ammoniumsalts thereof by treatment with quaternizing alkylating agents, such asmethyl iodide, dimethyl sulfate, or ethyl halogenides.

Optically active compounds of Formula 1 are suitably obtained by the useof starting materials which are already optically active. Preferably,the antipodes of HPI or those of compound 3 are used as startingcompounds. However, it is likewise possible to split thus-producedracemates of Formula 1 into the optical antipodes thereof. The method ofchemical separation is preferred. Thus, a racemate of Formula 1 can, forexample, be reacted with an optically active auxiliary agent, and thethus-obtained diastereomeric mixtures can be split in a suitable manner.For example, a racemate of Formula 1 carrying an acidic group (e.g., acarboxyl group) can be reacted with an optically active base or,conversely, a racemate 1 carrying a basic group (e.g., an amino group)can be reacted with an optically active acid. Suitable as opticallyactive bases are for example amines, such as quinine, cinchonidine,brucine, cinchonine, hydroxyhydrindamine, morphine, 1-phenylethylamine,1-naphthylethylamine, quinidine, strychnine, basic amino acids (such aslysine or arginine), or amino acid esters. Conversely, suitable asoptically active acids are the (+)- and (-)-forms of tartaric acid,dibenzoyltartaric acid, diacetyltartaric acid, camphoric acid,β-camphorsulfonic acid, mandelic acid, malic acid, 2-phenylbutyric acid,dinitrodiphenic acid, lactic acid, or quinic acid. The thus-obtaineddiastereomeric mixtures can subsequently be separated by selectivecrystallization or by manual screening. The isolated diastereomericcompounds can finally be separated hydrolytically into the desiredoptically active compounds of Formula 1.

The compounds 1 are effective preferably against cestodes andtrematodes. They can optionally be used against the following cestodes(arranged according to hosts):

1. Ruminants: Moniezia, Stilesia, Avitellina, Thysanosoma, Thysaniezia,cysticerci of Taenia sp., Coenurus cerebralis, Echinococci cysticerci.2. Equine animals: Anoplocephala. 3. Rodents: Hymenolepis (especially H.nana and H. diminuta). 4. Fowl: Davainea, Raillietina, Hymenolepis. 5.Canine and feline animals: Taenia (especially T. hydatigena, T.pisiformis, T. taeniaeformis, T. ovis, T. serialis, T. cervi, T.multiceps), Dipylidium (especially D. caninum), Echinococcus(particularly E. granulosus and E. multilocularis). 6. Man: Taenia (inparticular T. solium, T. saginata, T. serialis), Hymenolepis (especiallyH. nana and H. diminuta), Drepanidotaenia, Dipylidium, Diplopylidium,Coenurus (especially C. cerebralis), Diphyllobothrium (particularly D.latum), Echinococcus cysticerci (especially those of E. granulosus andE. multilocularis). Among the trematodes of significance from theviewpoints of human and veterinary medicine are primarily those of thefamily of the Schistosomidae, especially the genus Schistosoma (Sch.mansoni, Sch. haematobium, Sch. japonicum) which must be combated.Optionally, the genera Fasciola, Dicrocoelium, Clonorchis, Opisthorchis,Paragonimus, Paramphistomum, Echinostoma, and others can likewise betargets of attack.

The compounds 1 can be utilized, inter alia, in the following hostand/or intermediate host organisms for the combating of cestodes and/ortrematodes and/or the larvae thereof: Man, types of monkeys, the mostimportant domestic and wild animals, e.g., Canidae, such as dogs, foxes;Felidae, such as cats; Equidae, such as horses, donkeys, mules;Cervidae, such as roe deer, red deer, fallow deer; chamois; rodents;ruminants, such as cattle, sheep, goats; birds, such as chickens, ducks;pigs; fish.

As the biotope of the affectable parasites or the larvae thereof, worthmentioning are especially the gastrointestinal tract, e.g., stomach,intestine, pancreas and/or bile duct. However, other organs can also beeffected (e.g., liver, kidney, lungs, heart, spleen, lymph nodes, brain,spinal marrow, or testes), abdominal cavity, connective tissue,musculature, peritoneum, pleura, or diaphragm, lungs and/or bloodvessels; thus, the compounds 1, with good compatibility, are effectivefor example against Schistosoma sp. in the vascular system, againstHymenolepis microstoma in the bile duct, and T. hydatigena cysticerci inthe liver.

The compounds 1 can be utilized as such as in combination withpharmaceutically acceptable inert vehicles. Such vehicles can consist,for example, of capsules, solid diluents or fillers, sterile aqueousmedia and/or various nontoxic organic solvents.

Suitable forms of administration are, inter alia, tablets and dragees(optionally containing the effective agent in a timed-release form),effervescent tablets, capsules, granules, aqueous suspensions,injectable solutions, emulsions and suspensions, elixirs, syrups orpastes. The formulations for this purpose are produced conventionally,for example by adding the active agents to solvents and/or carriersubstances optionally with the use of emulsifiers and/or dispersingagents. Auxiliary substances in this connection are, for instance:water, nontoxic organic solvents (e.g., paraffins or alcohols, such asglycerin or polyethylene glycol), vegetable oils (e.g., sesame oil),solid carriers, such as natural or synthetic rock flours (e.g., talc orhighly disperse silicic acid), sugar, emulsifiers (e.g., ionic ornonionic compounds), dispersing agents (e.g., methylcellulose andpolyvinylpyrrolidone) and/or lubricants (e.g., magnesium stearate).Tablets can also contain additives, such as sweeteners, sodium citrate,calcium carbonate and dicalcium phosphate, together with furthersubstances such as amylose, gelatin, etc. Aqueous suspensions and/orelixirs can optionally be combined with flavor-ameliorating agents orcoloring substances. The compounds 1 can optionally also be administeredwithout, or almost without, auxiliary substances, for example incapsules.

The effective agents 1 are preferably administered orally, but it isalso possible to effect a parenteral, especially subcutaneous orintramuscular, as well as a dermal administration.

To combat adult cestodes, it is advantageous to administer the effectiveagents once or several times in daily amounts of 0.01-250 mg./kg.,preferably about 0.5-100 mg./kg. orally or subcutaneously. Whencombating the corresponding tapeworm larvae (cysticerci) and/or whencombating the Schistosoma, larger amounts of active agent may benecessary.

When giving larger amounts of effective agent, it is also possible todistribute smaller dosages over the day. Thus, instead of 1000 mg. in asingle dose, one can administer 5 separate doses of respectively 200 mg.In the veterinary medicine, it is also possible to give the effectiveagents together with the feed; suitably, premixes to be added to thefeed are produced. Here again, all customary additives can be utilized.

In certain cases, the aforementioned amounts must be changed, namely independence on the body weight and the type of application, but also onthe basis of the species and its individual behavior with respect to themedicinal agent and/or the type of its formulation and/or the instantand/or interval at which the agent is administered. Thus, it may besufficient in some cases to make do with less than the aforementionedminimum amount, while in other instances the above-mentioned upper limitmust be exceeded.

Depending on the type of application, the ratio between the compounds 1and the carrier and/or auxiliary agent employed can vary greatly. If acompound 1 is administered, for example, as a tablet or dragee, it ispossible to combine about 0.01-2500 mg. of active agent with about1-10,000 mg. of auxiliary agent. In contrast thereto, if a compound 1 isformulated as a premix for a medical feed, about 0.1-400 g. of compound1 can be used per about 1 kg. of carrier or auxiliary agent. Whenformulated in an injection fluid, a solution of 1 l. of liquid cancontain, depending on the type of solubilizer, about 0.5-100 g. of acompound 1; similarly, 1 l. of fluid can contain about 0.5-250 g. of acompound 1 dissolved and/or suspended therein.

The compounds 1 can be present in the formulations also in mixtures withother effective agents. Thus, it is useful to attain a broader spectrumof effectiveness optionally to add an effective agent active onnematodes, e.g., thiabendazole [2-(4-thiazolyl)benzimidazole] orpiperazine (or piperazine derivatives, such as N-methylpiperazine). Itis also possible to administer two or more compounds of general Formula1 in combination.

The anthelmintic effect of the substances will be explained in greaterdetail with reference to the following examples of their application:

A PHARMACOLOGICAL EXAMPLES

The following compounds were tested in these examples:

Effective Agent A 2-(4-aminobenzoyl)-HPI B 2-(3-fluorobenzoyl)-HPI C2-cyclohexylcarbonyl-HPI D 2-(4-tetrahydropyranylcarbonyl)-HPI

Effective Agent E 2-(3-thienylcarbonyl)-HPI F 2-(4-nitrobenzoyl)-HPI G2-nicotinoyl-HPI H 2-isobutyryl-HPI

The following products were used for comparison:

Quinacrine[2-methoxy-6-chloro-9-](1-methyl-4-diethylaminobutyl)-amino]-acridine],

Niclosamide [N-(2-chloro-4-nitrophenyl)-5-chlorosalicylamide],

Dichlorophen (2,2'-dihydroxy-5,5'-dichlorodiphenylmethane),

Lucanthone [1-(2-diethylaminoethylamino)-4-methylthioxanthonehydrochloride],

Niridazole [1-(5-nitro-2-thiazolyl)-imidazolidin-2-one], and

Stibophen [sodium antimony bis(pyrocatechol-2,4-disulfonate)].

EXAMPLE (a)

Hymenolepis nana, adults, larvae/mice

Hymenolepis microstoma, adults/mice

Hymenolepis diminuta/rats

Test animals experimentally infected with H. nana, H. microstoma, or H.diminuta are treated 1-3 days after infection (larvae) and/or after theprepatent period of the parasites has elapsed. The quantity of activeagent is applied as an aqueous suspension orally and subcutaneously,respectively.

The degree of effectiveness of the preparation is determined bycounting, after dissection, the worms which remained in the test animal,as compared to untreated control animals, and thus calculating theeffectiveness, in percent.

                  TABLE 1                                                         ______________________________________                                        (Example [a])                                                                                          Effective Minimum                                                             Dosage in mg./kg.                                    Effective                (Parasite Reduction                                  Agent      Parasite      >90%)                                                ______________________________________                                        A          H. nana - adults                                                                            20                                                              H. nana - larvae                                                                            100                                                             H. microstoma 50                                                              H. diminuta   25                                                   B          H. nana - adults                                                                            50                                                              H. diminuta   100                                                  C          H. nana - adults                                                                            20                                                              H. microstoma 100                                                             H. diminuta   25                                                   D          H. nana - adults                                                                            50                                                              H. diminuta   50                                                   E          H. nana - adults                                                                            250                                                             H. diminuta   250                                                  F          H. nana - adults                                                                            50                                                              H. diminuta   50                                                   G          H. nana - adults                                                                            20                                                   H          H. nana - adults                                                                            50                                                   Quinacrine H. diminuta   >1000                                                Niclosamide                                                                              H. nana - adults                                                                            500                                                  H. nana - larvae                                                                         ineffective                                                                   H. microstoma 500                                                  Dichlorophen                                                                             H. nana - adults                                                                            >1000                                                           H. diminuta   500                                                  ______________________________________                                    

EXAMPLE (b)

Taenia taeniaeformis, larvae (cysticerci)/mice

Mice infected experimentally with Taenia taeniaeformis larvae aretreated about 2-5 months after infection. The amount of active agent isapplied orally as an aqueous suspension.

The degree of activity of the preparation is determined by counting,after dissection, the number of living and killed-off larvae as comparedto untreated control animals, and then calculating the percentage ofeffectiveness.

                  TABLE 2                                                         ______________________________________                                        (Example [b])                                                                                Effective Minimum Dosage in                                    Effective      mg./kg. (Parasite Reduction                                    Agent          >90%)                                                          ______________________________________                                        A              100                                                            Quinacrine     ineffective                                                    Niclosamide    ineffective                                                    ______________________________________                                    

EXAMPLE (c)

Taenia spec./dogs

Dogs infected experimentally or naturally with Taenia hydatigena orTaenia pisiformis are treated after the prepatent period of theparasites has elapsed.

The amount of active agent is administered orally as pure effectivecompound in gelatin capsules.

                  TABLE 3                                                         ______________________________________                                        (Example [c])                                                                                Effective Minimum Dosage                                       Effective      in mg./kg. Parasite                                            Agent          Reduction >90%)                                                ______________________________________                                        A              10                                                             B              25                                                             C              10                                                             D              10                                                             E              10                                                             H              10                                                             Niclosamide    50                                                             ______________________________________                                    

The degree of effectiveness is determined by counting the worms excretedafter the treatment and the worms remaining in the test animal afterdissection, and then calculating the percentage of the excreted worms.

EXAMPLE (d)

Echinococcus multilocularis/dogs

Dogs infected experimentally with Echinococcus multilocularis aretreated between the 25th and 29th day after infection.

The amount of active agent is administered as the pure effectivecompound orally in gelatin capsules. The degree of effectiveness iscalculated analogously to Example (a).

                  TABLE 4                                                         ______________________________________                                        (Example 8 d])                                                                               Effective Minimum Dosage                                       Effective      in mg./kg. (Parasite                                           Agent          Reduction >90%)                                                ______________________________________                                        A              50                                                             B              50                                                             C              50                                                             Niclosamide    effectiveness                                                                 unsatisfactory to                                                             total lack in                                                                 effectiveness                                                  ______________________________________                                    

EXAMPLE (e)

Schistosoma mansoni/mice

Mice experimentally infected with Schistosoma mansoni are treated afterthe prepatent period of the parasites has elapsed.

The effective agent is administered orally in aqueous suspension. Theeffect is determined after dissection of the test animals by countingthe surviving parasites and the killed-off parasites.

                  TABLE 5                                                         ______________________________________                                        (Example [e])                                                                                Effective Minimum Dosage                                       Effective      in mg./kg. (Parasite                                           Agent          Reduction > 90%)                                               ______________________________________                                        A              100                                                            B              100                                                            C              100                                                            D              500                                                            H              500                                                            Niridazole     500                                                            Stibophen      1000                                                           ______________________________________                                    

In the following examples,

[α]=[α]_(D) ²⁰ in chloroform;

IR=infrared spectrum in KBr.

The temperatures herein are set forth in degrees Celsius.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

EXAMPLE 1

At 20°, 3.71 g. of 4-nitrobenzoyl chloride in 50 ml. of chloroform isadded dropwise to 4.04 g. of (±)-HPI and 2.8 ml. of triethylamine in 50ml. of chloroform. After one hour, the reaction mixture is extractedwith dilute hydrochloric acid and water. After drying and evaporation,(±)-2-(4-nitrobenzoyl)-HPI is obtained, m.p. 212°-213° (from methanol).

Analogously, the following products are prepared with the correspondingcarboxylic acid chlorides:

2-acetyl-HPI, m.p. 139°

2-propionyl-HPI

2-n-butyryl-HPI

2-isobutyryl-HPI, m.p. 120°

2-n-valeryl-HPI

2-isovaleryl-HPI

2-(2-methylbutyryl)-HPI

2-trimethylacetyl-HPI, m.p. 150°

2-n-hexanoyl-HPI

2-(2-methyl-n-valeryl)-HPI

2-(3-methyl-n-valeryl)-HPI

2-(4-methylvaleryl)-HPI

2-(1-ethyl-n-butyryl)-HPI

2-(2,2-dimethyl-n-butyryl)-HPI

2-(3,3-dimethyl-n-butyryl)-HPI, m.p. 113°

2-heptanoyl-HPI, m.p. 90°-91°

2-(2,2-dimethylvaleryl)-HPI, m.p. 129°

2-octanoyl-HPI

2-(2-n-propylhexanoyl)-HPI

2-decanoyl-HPI

2-(2-n-butylhexanoyl)-HPI, m.p. 96°

2-undecanoyl-HPI

2-hexadecanoyl-HPI, m.p. 101°-102°

2-octadecanoyl-HPI

2-trifluoroacetyl-HPI

2-chloroacetyl-HPI

2-dichloroacetyl-HPI, m.p. 151°-152°

2-trichloroacetyl-HPI, m.p. 184°-185°

2-(3-chloropropionyl)-HPI

2-tris(chloromethyl)acetyl-HPI, m.p. 133°-135°

2-(2-acetoxyacetyl)-HPI

2-(2-methoxyacetyl)-HPI, m.p. 135°

2-(2-ethoxyacetyl)-HPI

2-dimethylaminoacetyl-HPI

2-diethylaminoacetyl-HPI

2-methylethylaminoacetyl-HPI

2-(2-dimethylaminopropionyl)-HPI

2-(2-diethylaminopropionyl)-HPI

2-(3-dimethylaminopropionyl)-HPI

2-(3-diethylaminopropionyl)-HPI

2-(2-dimethylamino-n-butyryl)-HPI

2-(2-diethylamino-n-butyryl)-HPI

2-(4-dimethylamino-n-butyryl)-HPI

2-(4-diethylamino-n-butyryl)-HPI

2-(2-dimethylamino-n-valcryl)-HPI

2-(2-diethylamino-n-valeryl)-HPI

2-(5-dimethylamino-n-valeryl)-HPI

2-(5-diethylamino-n-valeryl)-HPI

2-(2-dimethylamino-n-hexanoyl)-HPI

2-(2-diethylamino-n-hexanoyl)-HPI

2-(6-dimethylamino-n-hexanoyl)-HPI

2-(6-diethylamino-n-hexanoyl)-HPI

2-(2-phenylacetyl)-HPI, m.p. 123°-124°

2-(2-hydroxy-2-phenylacetyl)-HPI

2-(2-acetoxy-2-phenylacetyl)-HPI, m.p. 101°-102°

2-phenoxyacetyl-HPI

2-(4-fluorophenoxyacetyl)-HPI

2-(3-chlorophenoxyacetyl)-HPI

2-(4-chlorophenoxyacetyl)-HPI, m.p. 159°-160°

2-(3-p-fluorophenoxypropionyl)-HPI

2-(3-m-chlorophenoxypropionyl)-HPI

2-(3-p-chlorophenoxypropionyl)-HPI

2-(thienyl-2-mercaptoacetyl)-HPI, m.p. 89°-90°

2-(thienyl-3-mercaptoacetyl)-HPI

2-crotonoyl-HPI

2-methacryloyl-HPI

2-vinylacetyl-HPI

2-cinnamoyl-HPI, m.p. 152°

2-phenylpropioloyl, m.p. 155°

2-phenoxycarbonyl-HPI, m.p. 136°-137°

2-ethoxalyl-HPI, m.p. 126°

2-cyclopropylcarbonyl-HPI, m.p. 148°

2-(2-acetoxycyclopropylcarbonyl)-HPI

2-(2-fluorocyclopropylcarbonyl)-HPI

2-cyclobutylcarbonyl-HPI, m.p. 154°-155°

2-(2-ketocyclobutylcarbonyl)-HPI

2-(3-ketocyclobutylcarbonyl)-HPI

2-(2-fluorocyclobutylcarbonyl)-HPI

2-(3-fluorocyclobutylcarbonyl)-HPI

2-(2-chlorocyclobutylcarbonyl)-HPI

2-(3-chlorocyclobutylcarbonyl)-HPI

2-(2-methylcyclobutylcarbonyl)-HPI

2-(3-methylcyclobutylcarbonyl)-HPI

2-(2,2-difluorocyclobutylcarbonyl)-HPI

2-(3,3-difluorocyclobutylcarbonyl)-HPI

2-(1-acetoxxycyclobutylcarbonyl)-HPI

2-(2-acetoxycyclobutylcarbonyl)-HPI

2-(3-acetoxycyclobutylcarbonyl)-HPI

2-(1-dimethylaminocyclobutylcarbonyl)-HPI

2-(2-dimethylaminocyclobutylcarbonyl)-HPI

2-(3-dimethylaminocyclobutylcarbonyl)-HPI

2-(2-methoxycarbonylcyclobutylcarbonyl)-HPI

2-(2-ethoxycarbonylcyclobutylcarbonyl)-HPI

2-(3-methoxycarbonylcyclobutylcarbonyl)-HPI

2-(3-ethoxycarbonylcyclobutylcarbonyl)-HPI

2-cyclopentylcarbonyl-HPI, m.p. 127°

2-(2-ketocyclopentylcarbonyl)-HPI

2-(3-ketocyclopentylcarbonyl)-HPI

2-(1-acetoxycyclopentylcarbonyl)-HPI

2-(2-acetoxycyclopentylcarbonyl)-HPI

2-(3-acetoxycyclopentylcarbonyl)-HPI

2-(2-fluorocyclopentylcarbonyl)-HPI

2-(3-fluorocyclopentylcarbonyl)-HPI

2-(2,2-difluorocyclopentylcarbonyl)-HPI

2-(3,3-difluorocyclopentylcarbonyl)-HPI

2-(2-chlorocyclopentylcarbonyl)-HPI

2-(3-chlorocyclopentylcarbonyl)-HPI

2-(2-methylcyclopentylcarbonyl)-HPI

2-(3-methylcyclopentylcarbonyl)-HPI

2-(1-dimethylaminocyclopentylcarbonyl)-HPI

2-(2-dimethylaminocyclopentylcarbonyl)-HPI

2-(3-dimethylaminocyclopentylcarbonyl)-HPI

2-(2-methoxycarbonylcyclopentylcarbonyl)-HPI

2-(2-ethoxycarbonylcyclopentylcarbonyl)-HPI

2-(3-methoxycarbonylcyclopentylcarbonyl)-HPI

2-(3-ethoxycarbonylcyclopentylcarbonyl)-HPI

2-cyclohexylcarbonyl-HPI, m.p. 136°-138°

2-(1-cyclohexenylcarbonyl)-HPI

2-(2-cyclohexenylcarbonyl)-HPI

2-(3-cyclohexenylcarbonyl)-HPI, m.p. 126°

2-(2-ketocyclohexylcarbonyl)-HPI

2-(3-ketocyclohexylcarbonyl)-HPI

2-(4-ketocyclohexylcarbonyl)-HPI, m.p. 154°

2-(1-acetoxycyclohexylcarbonyl)-HPI

2-(2-acetoxycyclohexylcarbonyl)-HPI

2-(3-acetoxycyclohexylcarbonyl)-HPI

2-(4-acetoxycyclohexylcarbonyl)-HPI

2-(1-formamidocyclohexylcarbonyl)-HPI

2-(2-formamidocyclohexylcarbonyl)-HPI

2-(3-formamidocyclohexylcarbonyl)-HPI

2-(4-formamidocyclohexylcarbonyl)-HPI

2-(1-dimethylaminocyclohexylcarbonyl)-HPI

2-(2-dimethylaminocyclohexylcarbonyl)-HPI

2-(3-dimethylaminocyclohexylcarbonyl)-HPI

2-(4-dimethylaminocyclohexylcarbonyl)-HPI

2-(2,4-bis-dimethylaminocyclohexylcarbonyl)-HPI

2-(3,4-bis-dimethylaminocyclohexylcarbonyl)-HPI

2-(3,5-bis-dimethylaminocyclohexylcarbonyl)-HPI

2-(1-diethylaminocyclohexylcarbonyl)-HPI

2-(2-diethylaminocyclohexylcarbonyl)-HPI

2-(3-diethylaminocyclohexylcarbonyl)-HPI

2-(4-diethylaminocyclohexylcarbonyl)-HPI

2-(3-methylethylaminocyclohexylcarbonyl)-HPI

2-(4-methylethylaminocyclohexylcarbonyl)-HPI

2-(2-fluorocyclohexylcarbonyl)-HPI

2-(3-fluorocyclohexylcarbonyl)-HPI

2-(4-fluorocyclohexylcarbonyl)-HPI

2-(2,2-difluorocyclohexylcarbonyl)-HPI

2-(3,3-difluorocyclohexylcarbonyl)-HPI

2-(4,4-difluorocyclohexylcarbonyl)-HPI

2-(2-chlorocyclohexylcarbonyl)-HPI

2-(3-chlorocyclohexylcarbonyl)-HPI

2-(4-chlorocyclohexylcarbonyl)-HPI

2-(2-bromocyclohexylcarbonyl)-HPI

2-(3-bromocyclohexylcarbonyl)-HPI

2-(4-bromocyclohexylcarbonyl)-HPI

2-(2-methylcyclohexylcarbonyl)-HPI

2-(3-methylcyclohexylcarbonyl)-HPI

2-(4-methylcyclohexylcarbonyl)-HPI

2-(2-methoxycarbonylcyclohexylcarbonyl)-HPI

2-(3-methoxycarbonylcyclohexylcarbonyl)-HPI

2-(4-methoxycarbonylcyclohexylcarbonyl)-HPI

2-(2-ethoxycarbonylcyclohexylcarbonyl)-HPI

2-(3-ethoxycarbonylcyclohexylcarbonyl)-HPI

2-(4-ethoxycarbonylcyclohexylcarbonyl)-HPI

2-cycloheptylcarbonyl-HPI, m.p. 91°

2-(4-dimethylaminocycloheptylcarbonyl)-HPI

2-(4-diethylaminocycloheptylcarbonyl)-HPI

2-(4-fluorocycloheptylcarbonyl)-HPI

2-(4-chlorocycloheptylcarbonyl)-HPI

2-cyclooctylcarbonyl-HPI, m.p. 109°

2-cyclononylcarbonyl-HPI

2-cyclodecylcarbonyl-HPI

2-cycloundecylcarbonyl-HPI, m.p. 150°-151°

2-cyclododecylcarbonyl-HPI

2-bicyclo[2,2,1]heptyl-2-carbonyl-HPI

2-bicyclo[2,2,2]octyl-2-carbonyl-HPI

2-(adamantylcarbonyl)-HPI, m.p. 159°-160°

2-(2-methylbenzoyl)-HPI

2-(3-methylbenzoyl)-HPI, m.p. 124°

2-(4-methylbenzoyl)-HPI, m.p. 183°-184°

2-(4-ethylbenzoyl)-HPI

2-(4-n-propylbenzoyl)-HPI

2-(4-isopropylbenzoyl)-HPI

2-(4-tert.-butylbenzoyl)-HPI, m.p. 198°

2-(4-phenylbenzoyl)-HPI

2-(3,4-dimethylbenzoyl)-HPI

2-(3,5-dimethylbenzoyl)-HPI

2-(3,4-diethylbenzoyl)-HPI

2-(3,5-diethylbenzoyl)-HPI

2-(2-fluorobenzoyl)-HPI, m.p. 129°

2-(3-fluorobenzoyl)-HPI, m.p. 164°-166°

2-(4-fluorobenzoyl)-HPI, m.p. 181°-182°

2-(2-chlorobenzoyl)-HPI

2-(3-chlorobenzoyl)-HPI, m.p. 181°-182°

2-(4-chlorobenzoyl)-HPI, m.p. 214°-215°

2-(2-bromobenzoyl)-HPI

2-(3-bromobenzoyl)-HPI

2-(4-bromobenzoyl)-HPI

2-(2-iodobenzoyl)-HPI

2-(3-iodobenzoyl)-HPI

2-(4-iodobenzoyl)-HPI

2-(2,3-difluorobenzoyl)-HPI

2-(2,4-difluorobenzoyl)-HPI

2-(2,5-difluorobenzoyl)-HPI

2-(2,6-difluorobenzoyl)-HPI

2-(3,4-difluorobenzoyl)-HPI

2-(3,5-difluorobenzoyl)-HPI

2-(3,4-dichlorobenzoyl)-HPI

2-(3,5-dichlorobenzoyl)-HPI, m.p. 165°-166°

2-(3,4-dibromobenzoyl)-HPI

2-(3,5-dibromobenzoyl)-HPI

2-(3,4,5-trifluorobenzoyl)-HPI

2-(2,3,4,5,6-pentafluorobenzoyl)-HPI, m.p. 156°

2-(2-hydroxybenzoyl)-HPI

2-(3-hydroxybenzoyl)-HPI, m.p. 153°

2-(4-hydroxybenzoyl)-HPI, m.p. 243°-245°

2-(3,4-dihydroxybenzoyl)-HPI

2-(3,5-dihydroxybenzoyl)-HPI, m.p. 250°-254° (decomposition)

2-(3,4,5-trihydroxybenzoyl)-HPI

2-(3-methoxybenzoyl)-HPI

2-(4-methoxybenzoyl)-HPI, m.p. 204°-205°

2-(3-acetoxybenzoyl)-HPI

2-(4-acetoxybenzoyl)-HPI

2-(3-trifluoroacetoxybenzoyl)-HPI

2-(4-trifluoroacetoxybenzoyl)-HPI

2-(3,4-dimethoxybenzoyl)-HPI

2-(3,5-dimethoxybenzoyl)-HPI

2-(3,4,5-trimethoxybenzoyl)-HPI

2-(4-phenoxybenzoyl)-HPI

2-(2-dimethylaminobenzoyl)-HPI

2-(3-dimethylaminobenzoyl)-HPI

2-(4-dimethylaminobenzoyl)-HPI, m.p. 225°-226°

2-(2-diethylaminobenzoyl)-HPI

2-(3-diethylaminobenzoyl)-HPI

2-(4-diethylaminobenzoyl)-HPI

2-(4-methylethylaminobenzoyl)-HPI

2-(3,4-bis-dimethylaminobenzoyl)-HPI

2-(3,5-bis-dimethylaminobenzoyl)-HPI

2-(2-formylaminobenzoyl)-HPI

2-(3-formamidobenzoyl)-HPI, m.p. 176°

2-(4-formamidobenzoyl)-HPI, m.p. 207°-208°

2-(2-acetamidobenzoyl)-HPI

2-(3-acetamidobenzyl)-HPI

2-(4-acetamidobenzoyl)-HPI, m.p. 247°-248°

2-(2-propionamidobenzoyl)-HPI

2-(3-propionamidobenzoyl)-HPI

2-(4-propionamidobenzoyl)-HPI

2-(3-butyramidobenzoyl)-HPI

2-(4-butyramidobenzoyl)-HPI

2-(3,4-bis-formamidobenzoyl)-HPI

2-(3,5-bis-formamidobenzoyl)-HPI

2-(3-isobutyramidobenzoyl)-HPI

2-(4-isobutyramidobenzoyl)-HPI

2-(2-pentanoylaminobenzoyl)-HPI

2-(3-pentanoylaminobenzoyl)-HPI

2-(4-pentanoylaminobenzoyl)-HPI

2-(2-hexanoylaminobenzoyl)-HPI

2-(3-hexanoylaminobenzoyl)-HPI

2-(4-hexanoylaminobenzoyl)-HPI

2-(2-octanoylaminobenzoyl)-HPI

2-(3-octanoylaminobenzoyl)-HPI

2-(4-octanoylaminobenzoyl)-HPI

2-(2-oleoylaminobenzoyl)-HPI

2-(3-oleoylaminobenzoyl)-HPI

2-(4-oleoylaminobenzoyl)-HPI

2-(2-methylmercaptobenzoyl)-HPI

2-(3-methylmercaptobenzoyl)-HPI

2-(4-methylmercaptobenzoyl)-HPI, m.p. 195°

2-(3-ethylmercaptobenzoyl)-HPI

2-(4-ethylmercaptobenzoyl)-HPI

2-(3,4-bis-methylmercaptobenzoyl)-HPI

2-(3,5-bis-methylmercaptobenzoyl)-HPI

2-(3,4,5-tris-methylmercaptobenzoyl)-HPI

2-(4-phenylmercaptobenzoyl)-HPI

2-(2-nitrobenzoyl)-HPI, m.p. 188°-189°

2-(3-nitrobenzoyl)-HPI, m.p. 172°

2-(3,4-dinitrobenzoyl)-HPI, m.p. 219°

2-(3,5-dinitrobenzoyl)-HPI, m.p. 251°-252°

2-(2-trifluoromethylbenzoyl)-HPI

2-(3-trifluoromethylbenzoyl)-HPI, m.p. 148°-149°

2-(4-trifluoromethylbenzoyl)-HPI

2-(2-cyanobenzoyl)-HPI

2-(3-cyanobenzoyl)-HPI

2-(4-cyanobenzoyl)-HPI, m.p. 214°-215°

2-(2-methoxycarbonylbenzoyl)-HPI

2-(3-methoxycarbonylbenzoyl)-HPI

2-(4-methoxycarbonylbenzoyl)-HPI, m.p. 178°

2-(2-ethoxycarbonylbenzoyl)-HPI

2-(3-ethoxycarbonylbenzoyl)-HPI

2-(4-ethoxycarbonylbenzoyl)-HPI

2-(3,4-bis-methoxycarbonylbenzoyl)-HPI

2-(3,5-bis-methoxycarbonylbenzoyl)-HPI

2-(2-azidobenzoyl)-HPI

2-(3-azidobenzoyl)-HPI

2-(4-azidobenzoyl)-HPI

2-(2-methoxysulfonylbenzoyl)-HPI

2-(3-methoxysulfonylbenzoyl)-HPI

2-(4-methoxysulfonylbenzoyl)-HPI

2-(2-ethoxysulfonylbenzoyl)-HPI

2-(3-ethoxysulfonylbenzoyl)-HPI

2-(4-ethoxysulfonylbenzoyl)-HPI

2-(2-chloro-4-nitrobenzoyl)-HPI, m.p. 176°-177°

2-(4-chloro-3-nitrobenzyl)-HPI, m.p. 192°-194°

2-(3-nitro-4-chlorobenzoyl)-HPI

2-(2-hydroxy-5-chlorobenzoyl)-HPI, m.p. 180°

2-naphthyl-1-carbonyl-HPI, m.p. 135°

2-naphthyl-2-carbonyl-HPI, m.p. 178°

2-(1,2,3,4-tetrahydronaphthyl-1-carbonyl)-HPI

2-(1,2,3,4-tetrahydronaphthyl-2-carbonyl)-HPI

2-(pyrryl-2-carbonyl)-HPI, m.p. 174°

2-(pyrryl-3-carbonyl)-HPI

2-(thienyl-2-carbonyl)-HPI, m.p. 132°-133°

2-(thienyl-3-carbonyl)-HPI, m.p. 142°-143°

2-(3-fluorothienyl-2-carbonyl)-HPI

2-(4-fluorothienyl-2-carbonyl)-HPI

2-(5-fluorothienyl-2-carbonyl)-HPI

2-(3-nitrothienyl-2-carbonyl)-HPI

2-(4-nitrothienyl-2-carbonyl)-HPI

2-(5-nitrothienyl-2-carbonyl)-HPI, m.p. 172°-173°

2-(3-dimethylaminothienyl-2-carbonyl)-HPI

2-(4-dimethylaminothienyl-2-carbonyl)-HPI

2-(3-formylaminothienyl-2-carbonyl)-HPI

2-(4-formylaminothienyl-2-carbonyl)-HPI

2-(3-methylthienyl-2-carbonyl)-HPI

2-(4-methylthienyl-2-carbonyl)-HPI

2-(5-methylthienyl-2-carbonyl)-HPI, m.p. 134°-136°

2-(2-methylthienyl-3-carbonyl)-HPI

2-(4-methylthienyl-3-carbonyl)-HPI

2-(5-methylthienyl-3-carbonyl)-HPI

2-(furyl-2-carbonyl)-HPI, m.p. 120°

2-(furyl-3-carbonyl)-HPI

2-(3-fluorofuryl-2-carbonyl)-HPI

2-(4-fluorofuryl-2-carbonyl)-HPI

2-(5-fluorofuryl-2-carbonyl)-HPI

2-(5-chlorofuryl-2-carbonyl)-HPI

2-(5-bromofuryl-2-carbonyl)-HPI, m.p. 209°

2-(5-nitrofuryl-2-carbonyl)-HPI, m.p. 182°

2-(indolyl-2-carbonyl)-HPI

2-(indolyl-3-carbonyl)-HPI

2-(indolyl-4-carbonyl)-HPI

2-(indolyl-5-carbonyl)-HPI, m.p. 235°

2-(indolyl-6-carbonyl)-HPI

2-(indolyl-7-carbonyl)-HPI

2-(pyrazolyl-3-carbonyl)-HPI

2-(pyrazolyl-4-carbonyl)-HPI

2-(5-methylpyrazolyl-3-carbonyl)-HPI, m.p. 201°

2-(4-methylpyrazolyl-3-carbonyl)-HPI

2-(4-methylimidazolyl-2-carbonyl)-HPI

2-(5-methylimidazolyl-2-carbonyl)-HPI

2-(2-methylimidazolyl-4-carbonyl)-HPI

2-(5-methylimidazolyl-4-carbonyl)-HPI

2-(imidazolyl-2-carbonyl)-HPI

2-(imidazolyl-4-carbonyl)-HPI

2-(thiazolyl-2-carbonyl)-HPI

2-(4-methylthiazolyl-2-carbonyl)-HPI

2-(5-methylthiazolyl-2-carbonyl)-HPI

2-(thiazolyl-4-carbonyl)-HPI, m.p. 154°

2-(2-methylthiazolyl-4-carbonyl)-HPI

2-(5-methylthiazolyl-4-carbonyl)-HPI

2-(thiazolyl-5-carbonyl)-HPI

2-(2-methylthiazolyl-5-carbonyl)-HPI

2-(4-methylthiazolyl-5-carbonyl)-HPI

2-(5-nitrothiazolyl-2-carbonyl)-HPI

2-(2,4-dimethylthiazolyl-5-carbonyl)-HPI, m.p. 162°-163°

2-(benzothiazolyl-2-carbonyl)-HPI

2-(benzothiazolyl-4-carbonyl)-HPI

2-(benzothiazolyl-5-carbonyl)-HPI

2-(isothiazolyl-3-carbonyl)-HPI

2-(4-methylisothiazolyl-3-carbonyl)-HPI

2-(5-methylisothiazolyl-3-carbonyl)-HPI

2-(isothiazolyl-4-carbonyl)-HPI

2-(3-methylisothiazolyl-4-carbonyl)-HPI

2-(5-methylisothiazolyl-4-carbonyl)-HPI

2-(isothiazolyl-5-carbonyl)-HPI

2-(3-methylisothiazolyl-5-carbonyl)-HPI

2-(4-methylisothiazolyl-5-carbonyl)-HPI

2-(oxazolyl-2-carbonyl)-HPI

2-(4-methyloxazolyl-2-carbonyl)-HPI

2-(5-methyloxazolyl-2-carbonyl)-HPI

2-(oxazolyl-4-carbonyl)-HPI

2-(2-methyloxazolyl-4-carbonyl)-HPI

2-(5-methyloxazolyl-4-carbonyl)-HPI

2-(oxazolyl-5-carbonyl)-HPI

2-(2-methyloxazolyl-5-carbonyl)-HPI

2-(4-methyloxazolyl-5-carbonyl)-HPI

2-(isoxazolyl-3-carbonyl)-HPI

2-(4-methylisoxazolyl-3-carbonyl)-HPI

2-(5-methylisoxazolyl-3-carbonyl)-HPI, m.p. 173°-174°

2-(isoxazolyl-4-carbonyl)-HPI

2-(3-methylisoxazolyl-4-carbonyl)-HPI

2-(5-methylisoxazolyl-4-carbonyl)-HPI

2-(isoxazolyl-5-carbonyl)-HPI

2-(3-methylisoxazolyl-5-carbonyl)-HPI

2-(4-methylisoxazolyl-5-carbonyl)-HPI

2-picolinoyl-HPT, hydrobromide, m.p. 163°

2-(3-fluoropicolinoyl)-HPI

2-(4-fluoropicolinoyl)-HPI

2-(5-fluoropicolinoyl)-HPI

2-(6-fluoropicolinoyl)-HPI

2-(3-diethylaminopicolinoyl)-HPI

2-(4-diethylaminopicolinoyl)-HPI

2-(5-diethylaminopicolinoyl)-HPI

2-(6-diethylaminopicolinoyl)-HPI

2-(3-formamidopicolinoyl)-HPI

2-(4-formamidopicolinoyl)-HPI

2-(5-formamidopicolinoyl)-HPI

2-(6-formamidopicolinoyl)-HPI

2-nicotinoyl-HPI, m.p. 172°

2-(2-fluoronicotinoyl)-HPI

2-(4-fluoronicotinoyl)-HPI

2-(5-fluoronicotinoyl)-HPI

2-(6-fluoronicotinoyl)-HPI

2-(2-chloronicotinoyl)-HPI

2-(4-chloronicotinoyl)-HPI, m.p. 158°

2-(5-chloronicotinoyl)-HPI

2-(6-chloronicotinoyl)-HPI

2-(2-hydroxynicotinoyl)-HPI

2-(4-hydroxynicotinoyl)-HPI

2-(5hydroxynicotinoyl)-HPI

2-(6-hydroxynicotinoyl)-HPI

2-(2-dimethylaminonicotinoyl)-HPI

2-(4-dimethylaminonicotinoyl)-HPI

2-(5-dimethylaminonicotinoyl)-HPI

2-(6-dimethylaminonicotinoyl)-HPI

2-(2-formamidonicotinoyl)-HPI

2-(4-formamidonicotinoyl)-HPI

2-(5-formamidonicotinoyl)-HPI

2-(6-formamidonicotinoyl)-HPI

2-(2-acetamidonicotinoyl)-HPI

2-(4-acetamidonicotinoyl)-HPI

2-(5-acetamidonicotinoyl)-HPI

2-(6-acetamidonicotinoyl)-HPI

2-isonicotinoyl-HPI, m.p. 140°-141°

2-(2,6-dichloroisonicotinoyl)-HPI, m.p. 207°-208°

2-(quinoylyl-2-carbonyl)-HPI, m.p. 198°-200°

2-(quinolyl-3-carbonyl)-HPI

2-(quinolyl-4-carbonyl)-HPI

2-(quinoyly-5-carbonyl)-HPI

2-(quinolyl-6-carbonyl)-HPI

2-(quinolyl-7-carbonyl)-HPI

2-(quinolyl-8-carbonyl)-HPI

2-(isoquinolyl-1-carbonyl)-HPI, m.p. 157°

2-(isoquinolyl-3-carbonyl)-HPI

2-(pyridazinyl-3-carbonyl)-HPI

2-(pyridazinyl-4-carbonyl)-HPI

2-(pyrimidinyl-2-carbonyl)-HPI

2-(pyrimidinyl-4-carbonyl)-HPI

2-(pyrimidinyl-5-carbonyl)-HPI

2-(pyrazinyl-2-carbonyl)-HPI, m.p. 153°-154°

2-(purinyl-2-carbonyl)-HPI

2-(purinyl-6-carbonyl)-HPI

2-(purinyl-8-carbonyl)-HPI

2-nalidixinyl-HPI[═2-(1-ethyl-7-methyl-1,8-naphthyridin-4-one-3-carbonyl)-HPI]

2-(dioxanyl-2-carbonyl)-HPI

2-(4-methylpiperazinyl-1-carbonyl)-HPI, hydrochloride, m.p. 290°

2-(dihydrofuryl-2-carbonyl)-HPI

2-(tetrahydrofuryl-2-carbonyl)-HPI

2-(tetrahydrofuryl-3-carbonyl)-HPI

2-(1-methyl-1,2,5,6-tetrahydropyridyl-3-carbonyl)-HPI, hydrochloride,m.p. 211°

2-(1-methyl-1,4,5,6-tetrahydropyridyl-3-carbonyl)-HPI

2-(1-methylpiperidyl-2-carbonyl)-HPI

2-(1-methylpiperidyl-3-carbonyl)-HPI

2-(1-methylpiperidyl-4-carbonyl)-HPI

2-(1-ethylpiperidyl-2-carbonyl)-HPI

2-(1-ethylpiperidyl-3-carbonyl)-HPI

2-(1-ethylpiperidyl-4-carbonyl)-HPI

2-(1-benzylpiperidyl-2-carbonyl)-HPI

2-(1-benzylpiperidyl-3-carbonyl)-HPI

2-(1-benzylpiperidyl-4-carbonyl)-HPI

2-(1-formylpiperidyl-3-carbonyl)-HPI

2-(1-formylpiperidyl-4-carbonyl)-HPI, m.p. 160°

2-(1-acetylpiperidyl-2-carbonyl)-HPI

2-(1-acetylpiperidyl-3-carbonyl)-HPI

2-(1-acetylpiperidyl-4-carbonyl)-HPI

2-(1-hexanoylpiperidyl-2-carbonyl)-HPI

2-(1-hexanoylpiperidyl-3-carbonyl)-HPI

2-(1-hexanoylpiperidyl-4-carbonyl)-HPI

2-(1-octanoylpiperidyl-2-carbonyl)-HPI

2-(1-octanoylpiperidyl-3-carbonyl)-HPI

2-(1-octanoylpiperidyl-4-carbonyl)-HPI

2-(1-oleoylpiperidyl-2-carbonyl)-HPI

2-(1-oleoylpiperidyl-3-carbonyl)-HPI

2-(1-oleoylpiperidyl-4-carbonyl)-HPI

2-[1-(methoxyacetyl)-piperidyl-2-carbonyl)-HPI

2-[1-(methoxyacetyl)-piperidyl-3-carbonyl]-HPI

2-[1-(methoxyacetyl)-piperidyl-4-carbonyl]-HPI

2-[1-(ethoxyacetyl)-piperidyl-2-carbonyl]-HPI

2-[1-(ethoxyacetyl)-piperidyl-3-carbonyl]-HPI

2-[1-(ethoxyacetyl)-piperidiyl-4-carbonyl]-HPI

2-(tetrahydropyranyl-2-carbonyl)-HPI

2-(tetrahydropyranyl-3-carbonyl)-HPI

2-(tetrahydropyranyl-4-carbonyl)-HPI, m.p. 172°

2-(chromone-2-carbonyl)-HPI, m.p. 155°-156°

2-(tetrahydrothiopyranyl-2-carbonyl)-HPI

2-(tetrahydrothiopyranyl-3-carbonyl)-HPI

2-(tetrahydrothiopyranyl-4-carbonyl)-HPI, m.p. 168°

2-(1,2,3-thiadiazolyl-4-carbonyl)-HPI

2-(2,1,3-benzothiadiazolyl-5-carbonyl)-HPI, m.p. 144°

EXAMPLE 2

At 140° (bath temperature), 1 ml. of phosphorus trichloride is droppedto a solution of 6.1 g. of HPI and 5.5 g. of 5-chlorosalicyclic acid in50 ml. of chlorobenzene. The mixture is refluxed for one hour,evaporated, the residue is chromatographed over silica gel withchloroform as the eluent, and the product is2-(5-chloro-2-hydroxybenzoyl)-HPI, m.p. 180° (from isopropanol).

EXAMPLE 3

10.1 g. of HPI, 6.75 g. of isonicotinic acid, and 5.5 g. of silicontetrachloride are refluxed in 150 ml. of pyridine for one hour. Themixture is then poured on ice, extracted with chloroform, and washedwith water. After drying over sodium sulfate and evaporation,2-(isonicotinoyl)-HPI is obtained, m.p. 140°-141° (from ethanol).

EXAMPLE 4

6.1 g. of HPI and 1.4 g. of formic acid are heated in 100 ml. of toluenefor 5 hours; the thus-produced water is distilled off. The mixture iscooled, thus obtaining 2-formyl-HPI, m.p. 206° (from ethanol).

EXAMPLE 5

4.04 g. of HPI and 3.4 g. of cyclohexane-1,2-transdicarboxylic acidanhydride are dissolved at 20° in respectively 25 ml. of methylenechloride and then combined. The mixture is allowed to stand, evaporated,and 2-(2-trans-carboxycyclohexylcarbonyl)-HPI is obtained, m.p.208°-210° (from ethyl acetate/petroleum ether).

Analogously, but with 6 hours of refluxing in dioxane,2-(2-cis-carboxycyclohexylcarbonyl)-HPI, m.p. 194°-196°, is obtainedwith cyclohexane-1,2-cis-dicarboxylic acid anhydride.

Analogously, with the use of

cyclobutane-1,2-dicarboxylic acid anhydride

cyclopentane-1,2-dicarboxylic acid anhydride

cycloheptane-1,2-dicarboxylic acid anhydride

phthalic acid anhydride

succinic acid anhydride,

the following final products can be produced:

2-(2-trans-carboxycyclopentylcarbonyl)-HPI

2-(2-trans-carboxycycloheptylcarbonyl)-HPI

2-(2-cis-carboxycyclobutylcarbonyl)-HPI

2-(2-cis-carboxycyclopentylcarbonyl)-HPI

2-(2-cis-carboxycycloheptylcarbonyl)-HPI

2-(2-carboxybenzoyl)-HPI

2-(3-carboxypropionyl)-HPI.

EXAMPLE 6

Analogously to Example 1, the following final products are obtained fromthe two antipodes (+)-HPI and (-)-HPI and the corresponding acidchlorides:

(+)-2-acetyl-HPI

(-)-2-acetyl-HPI

(+)-2-propionyl-HPI

(-)-2-propionyl-HPI

(+)-2-isobutyryl-HPI

(-)-2-isobutyryl-HPI

(+)-2-trimethylacetyl-HPI

(-)-2-trimethylacetyl-HPI

(+)-2-(3,3-dimethyl-n-butyryl)-HPI

(-)-2-(3,3-dimethyl-n-butyryl)-HPI

(+)-2-heptanoyl-HPI

(-)-2-heptanoyl-HPI

(+)-2-(thienyl-2-mercaptoacetyl)-HPI

(-)-2-(thienyl-2-mercaptoacetyl)-HPI

(+)-2-cyclopropylcarbonyl-HPI

(-)-2-cyclopropylcarbonyl-HPI

(+)-2-cyclobutylcarbonyl-HPI

(-)-2-cyclobutylcarbonyl-HPI

(+)-2-cyclopentylcarbonyl-HPI

(-)-2-cyclopentylcarbonyl-HPI

(+)-2-cyclohexylcarbonyl-HPI, m.p. 108°-110°; [α]=+145.2°

(-)-2-cyclohexylcarbonyl-HPI, m.p. 107°-108°; [α]=-146.9°

(+)-2-(4-formamidocyclohexylcarbonyl)-HPI

(-)-2-(4-formamidocyclohexylcarbonyl)-HPI

(+)-2-cycloheptylcarbonyl-HPI

(-)-2-cycloheptylcarbonyl-HPI

(+)-2-cyclooctylcarbonyl-HPI

(-)-2-cyclooctylcarbonyl-HPI

(+)-2-(4-methylbenzoyl)-HPI, m.p. 108°-181°; [α]=+29.2°

(-)-2-(4-methylbenzoyl)-HPI, m.p. 181°-182°; [α]=-28.5°

(+)-2-(4-tert.-butylbenzoyl)-HPI, m.p. 181°-182°; [α]=+21.5°

(-)-2-(4-tert.-butylbenzoyl)-HPI, m.p. 168°-169°; [α]=-20.5°

(+)-2-(2-fluorobenzoyl)-HPI, m.p. 155°-156°; [α]=+49.1°

(-)-2-(2-fluorobenzoyl)-HPI, m.p. 159°-161°; [α]=-49.9°

(+)-2-(3-fluorobenzoyl)-HPI, m.p. 156°-158° (sintering at 148°);[α]=+40.2°

(-)-2-(3-fluorobenzoyl)-HPI, m.p. 156; [α]=-41.6°

(+)-2-(4-fluorobenzoyl)-HPI, m.p. 200°-201°; [α]=+33.5°

(-)-2-(4-fluorobenzoyl)-HPI, m.p. 202°-203°; [α]=-32.6°

(+)-2-(3-chlorobenzoyl)-HPI

(-)-2-(3-chlorobenzoyl)-HPI

(+)-2-(4-chlorobenzoyl)-HPI, m.p. 231°-232°; [α]=+20.4°

(-)-2-(4-chlorobenzoyl)-HPI, m.p. 233°-234°; [α]-20.7°

(+)-2-(3-hydroxybenzoyl)-HPI

(-)-2-(3-hydroxybenzoyl)-HPI

(+)-2-(4-hydroxybenzoyl)-HPI

(-)-2-(4-hydroxybenzoyl)-HPI

(+)-2-(4-methoxybenzoyl)-HPI, m.p. 215°; [α]=+19.8°

(-)-2-(4-methoxybenzoyl)-HPI, m.p. 216°; [α]=-18.7°

(+)-2-(3-dimethylaminobenzoyl)-HPI

(-)-2-(3-dimethylaminobenzoyl)-HPI

(+)-2-(4-dimethylaminobenzoyl)-HPI

(-)-2-(4-dimethylaminobenzoyl)-HPI

(+)-2-(4-diethylaminobenzoyl)-HPI

(-)-2-(4-diethylaminobenzoyl)-HPI

(+)-2-(2-formamidobenzoyl)-HPI

(-)-2-(2-formamidobenzoyl)-HPI

(+)-2-(3-formamidobenzoyl)-HPI

(-)-2-(3-formamidobenzoyl)-HPI

(+)-2-(4-formamidobenzoyl)-HPI, m.p. 193°; [α]=+8.6°

(-)-2-(4-formamidobenzoyl)-HPI, m.p. 193°; [α]=-8.4°

(+)-2-(2-acetamidobenzoyl)-HPI

(')-2-(2-acetamidobenzoyl)-HPI

(+)-2-(3-acetamidobenzoyl)-HPI

(-)-2-(3-acetamidobenzoyl)-HPI

(+)-2-(4-acetamidobenzoyl)-HPI

(-)-2-(4-acetamidobenzoyl)-HPI

(+)-2-(2-nitrobenzoyl)-HPI

(-)-2-(2-nitrobenzoyl)-HPI

(+)-2-(3-nitrobenzoyl)-HPI, m.p. 139°; [α]=+2.9° (from the (-)-base)

(-)-2-(3-nitrobenzoyl)-HPI, m.p. 139°; [α]=-2.9° (from the (+)-base)

(+)-2-(4-nitrobenzoyl)-HPI, m.p. 223°-224°; [α]=+18.5°

(-)-2-(4-nitrobenzoyl)-HPI, m.p. 223°-224°; [α]=-21.4°

(+)-2-thienyl-2-carbonyl)-HPI

(-)-2-(thienyl-2-carbonyl)-HPI

(+)-2-(thienyl-3-carbonyl)-HPI

(-)-2-(thienyl-3-carbonyl)-HPI

(+)-2-(5-methylthienyl-2-carbonyl)-HPI

(-)-2-(5-methylthienyl-2-carbonyl)-HPI

(+)-2-(furyl-2-carbonyl)-HPI

(-)-2-(furyl-2-carbonyl)-HPI

(+)-2-picolinoyl-HPI

(-)-2-picolinoyl-HPI

(+)-2-nicotinoyl-HPI, m.p. 148°; [α]=+25.5°

(-)-2-nicotinoyl-HPI, m.p. 156°; [α]=-28.4°

(+)-2-isonicotinoyl-HPI

(-)-2-isonicotinoyl-HPI

(+)-2-nicotinoyl-HPI-1'-N-oxide

(-)-2-nicotinoyl-HPI-1'-N-oxide

(+)-2-(tetrahydropyranyl-4-carbonyl)-HPI

(-)-2-(tetrahydropyranyl-4-carbonyl)-HPI

(+)-2-(tetrahydrothiopyranyl-4-carbonyl)-HPI

(-)-2-(tetrahydrothiopyranyl-4-carbonyl)-HPI

(+)-2-(N-formylpiperidyl-4-carbonyl)-HPI

(-)-2-(N-formylpiperidyl-4-carbonyl)-HPI.

EXAMPLE 7

3.8 g. of 3-trifluoromethylbenzoyl fluoride in 50 ml. of chloroform isadded dropwise to 4.04 g. of HPI and 2.8 ml. of triethylamine in 50 ml.of chloroform. The reaction mixture is maintained for one hour at 20°,extracted with dilute hydrochloric acid and water, evaporated, and2-(3-trifluoromethylbenzoyl)-HPI is thus obtained, m.p. 148°-149° (fromethanol).

EXAMPLE 8

Analogously to Example 1, 2-(4-nitrobenzoyl)-HPI (m.p. 212°-213°) isproduced from HPI and p-nitrobenzoyl bromide in chloroform in thepresence of triethylamine after a reaction period of two hours.

EXAMPLE 9

Analogously to Example 1, 2-(4-nitrobenzoyl)-HPI (m.p. 212°-213°) isobtained at 40° (2 hours) from HPI and p-nitrobenzoyl iodide inchloroform in the presence of triethylamine.

EXAMPLE 10

Under nitrogen at 20°, 12 ml. of 20% butyllithium solution in hexane isadded dropwise to 8.5 g. ofN-(2-chloroacetyl-1,2,3,4-tetrahydroisoquinolinyl-1-methyl)-4-fluorobenzamide[obtainable by hydrogenation of1-cyano-2-(4-fluorobenzoyl)-1,2-dihydroisoquinoline on Raney nickel at100° and under 250 atmospheres, and reaction of the thus-formedN-(1,2,3,4-tetrahydroisoquinolinyl-1-methyl)-4-fluorobenzamide withchloroacetyl chloride in chloroform in the presence of triethylamine] in300 ml. abs. THF. The mixture is stirred for 2 hours at 20° and refluxedfor another 12 hours. After the addition of water, the solvent isremoved and the residue taken up in chloroform. Then, the mixture isextracted with water, dried, and evaporated, thus obtaining2-(4-fluorobenzoyl)-HPI, m.p. 181°-182° (from methanol).

Analogously, (-)-2-(4-fluorobenzoyl)-HPI can be obtained from 8.5 g. of(+)-N-(2-chloroacetyl-1,2,3,4-tetrahydroisoquinolinyl-1-methyl)-4-fluorobenzamideand butyllithium, m.p. 202°-203°; [α]=-32.6°.

In an analogous manner, 2-(4-methylbenzoyl)-HPI, m.p. 183°-184°; isproduced fromN-(2-bromoacetyl-1,2,3,4-tetrahydroisoquinolinyl-1-methyl)-4-methylbenzamideof fromN-(2-iodoacetyl-1,2,3,4-tetrahydroisoquinolinyl-1-methyl)-4-methylbenzamideor fromN-(2-p-toluenesulfonyloxyacetyl-1,2,3,4-tetrahydroisoquinolinyl-1-methyl)-p-methylbenzamideand butyllithium.

Furthermore, 2-cyclohexylcarbonyl-HPI, m.p. 136°-138° is obtainedanalogously fromN-(2-chloroacetyl-1,2,3,4-tetrahydroisoquinolinyl-1-methyl)-cyclohexylcarboxylicacid amide with butyllithium.

EXAMPLE 11

15 g. of a nickel-aluminum alloy (1:1) is introduced in incrementalportions and under agitation into 200 ml. of 20% sodium hydroxidesolution within 5 minutes; the mixture is maintained at 80° for 45minutes, then allowed to settle, decanted off, washed with water, and1,000 ml. of 1% (-)-tartaric acid solution is added thereto, adjusted topH 5 with 1 N sodium hydroxide solution. The mixture is heated underagitation for 90 minutes to 80°, decanted, and washed with water andmethanol. The thus-obtained (-)-tartaric acid-Raney nickel catalyst isadded to a solution of 322 mg. of2-(4-fluorobenzoyl)-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]isoquinoline(obtainable by dehydrogenation of (±)- or of (+)-2-(4-fluorobenzoyl)-HPIwith sulfur) in 40 ml. of methanol. The reaction mixture is hydrogenatedunder normal pressure and at room temperature. After the catalyst hasbeen filtered off and the solvent evaporated,(-)-2-(4-fluorobenzoyl)-HPI is obtained in 23% optical purity; m.p.190°-193°; [α]=-7.5°

Analogously, (-)-2-cyclohexylcarbonyl-HPI is obtained in 20% opticalpurity; m.p. 122°-127°; [α]=-29.3°; from2-cyclohexylcarbonyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]-isoquinoline(m.p. 140°-141°).

EXAMPLE 12

Analogously to Example 11, 322 mg. of2-(4-fluorobenzoyl)-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]isoquinolineis hydrogenated in 40 ml. of methanol in the presence of 300 mg. ofRaney nickel, thus obtaining racemic 2-(4-fluorobenzoyl)-HPI, m.p.181°-182°.

Analogously, 2-cyclohexylcarbonyl-HPI, m.p. 136°-138°, is produced from2-cyclohexylcarbonyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]isoquinoline.

EXAMPLE 13

A solution of 67.7 g. of 2-(4-nitrobenzoyl)-HPI in 1,500 ml. of methanolis hydrogenated on 12 g. of 5% palladium charcoal at 20° under normalpressure. The catalyst is filtered off, the filtrate is evaporated, andthe residue yields 2-(4-aminobenzoyl)-HPI, m.p. 212°-213° (fromethanol); hydrochloride, m.p. 165°-166° (decomposition); sulfate, m.p.234°-235°; isethionate, m.p. 233°-234°.

Analogously, the following products are obtained by hydrogenation of thecorresponding nitro compounds:

2-aminoacetyl-HPI

2-(2-aminopropionyl)-HPI

2-(3-aminopropionyl)-HPI

2-(2-amino-n-butyryl)-HPI

2-(4-amino-n-butyryl)-HPI

2-(2-amino-n-valeryl)-HPI

2-(5-amino-n-valeryl)-HPI

2-(3-aminophenoxyacetal)-HPI

2-(4-aminophenoxyacetyl)-HPI

2-(2-aminocyclopropylcarbonyl)-HPI

2-(1-aminocyclobutylcarbonyl)-HPI

2-(2-aminocyclobutylcarbonyl)-HPI

2-(3-aminocyclobutylcarbonyl)-HPI

2-(1-aminocyclopentylcarbonyl)-HPI

2-(2-aminocyclopentylcarbonyl)-HPI

2-(3-aminocyclopentylcarbonyl)-HPI

2-(1-aminocyclohexylcarbonyl)-HPI

2-(2-aminocyclohexylcarbonyl)-HPI

2-(3-aminocyclohexylcarbonyl)-HPI

cis-2-(4-aminocyclohexylcarbonyl)-HPI, amorphous; IR: 3500, 3300 and1645 cm⁻¹

trans-2-(4-aminocyclohexylcarbonyl)-HPI, m.p. 284°

2-(4-aminocycloheptylcarbonyl)-HPI

2-(2-aminobenzoyl)-HPI, hydrobromide, m.p. 279°-280°

2-(3-aminobenzoyl)-HPI, m.p. 161°-162°

(+)-2-(3-aminobenzoyl)-HPI, m.p. 164°-165°; [α]=+35.9° (from the(-)-nitro antipode)

(-)-2-(3-aminobenzoyl)-HPI, m.p. 164°-165°; [α]=-36.5° (from the(+)-nitro antipode)

(+)-2-(4-aminobenzoyl)-HPI, m.p. 231°-232°; [α]=+23.1°; hydrobromide:m.p. starting with 193° (decomposition); isethionate: m.p. 200°-210°;[α]=+16.0°

(-)-2-(4-aminobenzoyl)-HPI, m.p. 231°-232°; [α]=-23.0°; hydrobromide:m.p. starting with 205° (decomposition); isethionate: m.p. 200°-210°;[α]=-16.3°

2-(3,4-diaminobenzoyl)-HPI, m.p. 143°

2-(3,5-diaminobenzoyl)-HPI, m.p. 235°-236°

2-(2-chloro-4-aminobenzoyl)-HPI, m.p. 145°; hydrochloride: m.p.181°-182°

2-(2-chloro-5-aminobenzoyl)-HPI

2-(3-chloro-4-aminobenzoyl)-HPI

2-(3-chloro-5-aminobenzoyl)-HPI

2-(2-amino-3-chlorobenzoyl)-HPI

2-(2-amino-4-chlorobenzoyl)-HPI

2-(2-amino-5-chlorobenzoyl)-HPI

2-(3-amino-4-chlorobenzoyl)-HPI; hydrobromide: m.p. 208°-210°

2-(3-aminothienyl-2-carbonyl)-HPI

2-(4-aminothienyl-2-carbonyl)-HPI

2-(4-aminotetrahydrothiopyranyl-4-carbonyl)-HPI, m.p. 157°-158°

2-(4-aminonicotinoyl)-HPI

2-(5-aminonicotinoyl)-HPI.

EXAMPLE 14

2.4 g. of acetyl chloride in 100 ml. of chloroform is added to 9.6 g. of2-(4-aminobenzoyl)-HPI and 3.1 g. of triethylamine in 300 ml. ofchloroform; the mixture is allowed to stand for 2 hours at 20°.Thereafter, another 2.4 g. of acetyl chloride is added, along with 3.1g. of triethylamine, and the mixture is refluxed for 3 hours, whereuponit is washed with dilute hydrochloric acid and water. After the solventhas been evaporated, 2-(4-acetamidobenzoyl)-HPI is obtained, m.p.247°-248° (from acetone).

Analogously, the following compounds are produced by acylation:

2-acetamidoacetyl-HPI

2-(1-acetamidocyclohexylcarbonyl)-HPI

2-(2-acetamidocyclohexylcarbonyl)-HPI

2-(3-acetamidocyclohexylcarbonyl)-HPI

2-(4-acetamidocyclohexylcarbonyl)-HPI

2-(4-propionamidocyclohexylcarbonyl)-HPI

2-(4-pentanoylaminocyclohexylcarbonyl)-HPI

2-(4-hexanoylaminocyclohexylcarbonyl)-HPI

2-(4-octanoylaminocyclohexylcarbonyl)-HPI

2-(4-oleoylaminocyclohexylcarbonyl)-HPI

2-(2-sulfaminoacetyl)-HPI (with chlorosulfonic acid)

2-(4-sulfaminocyclohexylcarbonyl)-HPI

2-(3-sulfaminobenzoyl)-HPI

2-(4-sulfaminobenzoyl)-HPI

2-(1-sulfopiperidyl-4-carbonyl)-HPI.

EXAMPLE 15

A solution of 3.5 g. of 2-(4-methylnitrosaminobenzoyl)-HPI (produced byintroducing the nitroso group into 2-(4-methylaminobenzoyl)-HPI) in 5ml. of acetic acid is gradually added under vigorous agitation to 2.7 g.of zinc dust in 5 ml. of water. The mixture was stirred for 2 hours at20°, heated to 80°, and filtered in the hot condition. The residue iswashed with 5% hydrochloric acid, and the combined filtrates arerendered alkaline and extracted with chloroform. The extract is washedneutral with water and evaporated, thus obtaining2-[4-(1-methylhydrazino)-benzoyl]-HPI.

Analogously, the following products are obtained:

2-[2-(1-methylhydrazino)-benzoyl]-HPI

2-[3-(1-methylhydrazino)-benzoyl]-HPI

2-[4-(1-ethylhydrazino)-benzoyl]-HPI.

EXAMPLE 16

8 ml. of 30% strength hydrogen peroxide and 0.8 ml. of 6 N NaOH areadded to 5 g. of 2-(4-cyanobenzoyl)-HPI in 20 ml. of ethanol. Themixture heats up while giving off oxygen. The temperature is maintainedfor 1 hour between 40° and 50°; then the mixture is cooled and combinedwith 5 ml. of water, thus producing 2-(4-carboxamidobenzoyl)-HPI.

Analogously, 2-(3-carboxamidobenzoyl)-HPI is prepared from2-(3-cyanobenzoyl)-HPI.

EXAMPLE 17

A mixture of 8 g. of 2-(4-methoxycarbonylbenzoyl)-HPI and 500 ml. of 10%sodium hydroxide solution is agitated for 12 hours at 20°. The reactionmixture is filtered off from the undissolved matter, acidified withhydrochloric acid, and extracted with chloroform. The residue ispurified by chromatography on silica gel (eluent: chloroform/methanol),thus obtaining 2-(4-carboxybenzoyl)-HPI, m.p. 251°.

Analogously, the following compounds are obtained by alkalinesaponification:

2-(2-carboxycyclopropylcarbonyl)-HPI

2-(2-carboxycyclobutylcarbonyl)-HPI

2-(3-carboxycyclobutylcarbonyl)-HPI

2-(2-carboxycyclopentylcarbonyl)-HPI

2-(3-carboxycyclopentylcarbonyl)-HPI

trans-2-(2-carboxycyclohexylcarbonyl)-HPI, m.p. 208°-210°

cis-2-(2-carboxycyclohexylcarbonyl)-HPI, m.p. 194°-196°

2-(3-carboxycyclohexylcarbonyl)-HPI

2-(4-carboxycyclohexylcarbonyl)-HPI

2-(2-carboxybenzoyl)-HPI

2-(3-carboxybenzoyl)-HPI

2-(3,4-dicarboxybenzoyl)-HPI

2-(3,5-dicarboxybenzoyl)-HPI.

EXAMPLE 18

A solution of 32 g. of 2-(4-hydroxybenzoyl)-HPI in 150 ml. ofmethanol/water (10:1) is combined with an excess of etherealdiazomethane solution until a slight yellow coloring remains. Themixture is then evaporated, the residue taken up in ether, washed withdilute sodium hydroxide solution and water, dried with sodium sulfate,evaporated, and the product thus obtained is 2-(4-methoxybenzoyl)-HPI,m.p. 204°-205°.

EXAMPLE 19

At -5° to -10°, 7.5 g. of boron tribromide is added dropwise to 5.4 g.of 2-(4-methoxybenzoyl)-HPI in 100 ml. of methylene chloride. Themixture is agitated for one hour at 20° and poured on ice. The organicphase is separated, and the aqueous phase is extracted several timeswith methylene chloride. The combined organic phases are dried oversodium sulfate and then evaporated. From the residue,2-(4-hydroxybenzoyl)-HPI is obtained, m.p. 243°-245° (from ethanol).

EXAMPLE 20

A mixture of 3.22 g. of 2-(4-hydroxybenzoyl)-HPI, 1.02 g. of aceticanhydride, and 100 ml. of pyridine is refluxed for 3 hours; the mixtureis then poured on ice, extracted with ether, washed with water, anddried over sodium sulfate, yielding 2-(4-acetoxybenzoyl)-HPI.

EXAMPLE 21

A mixture of 4.8 g. of 2-(4-aminobenzoyl)-HPI and 1.5 g. of 33%formaldehyde solution in 200 ml. of methanol is hydrogenated on 0.5 g.of 5% palladium charcoal. Thereafter, the mixture is filtered, thesolvent removed by evaporation, and the residue purified bychromatography on silica gel (eluent: chloroform), thus obtaining2-(4-methylaminobenzoyl)-HPI, m.p. 220°.

EXAMPLE 22

Analogously to Example 21, 2-(4-dimethylaminobenzoyl)-HPI, m.p.225°-226°, is produced from 4.8 g. of 2-(4-aminobenzoyl)-HPI and 4 g. of33% formaldehyde solution.

EXAMPLE 23

Within 2 hours, 3.2 g. of 2-(4-aminobenzoyl)-HPI in 100 ml. of dioxaneis combined, under the exclusion of moisture, with 2.5 g. of dimethylsulfate and then stirred for 15 hours at 100°. The mixture is thencooled, 1.4 g. of potassium hydroxide in 5 ml. of water is addedthereto, and the mixture is extracted with chloroform. Afterevaporation, 2-(4-dimethylaminobenzoyl)-HPI is obtained, m.p. 225°-226°.

EXAMPLE 24

10.4 g. of 2-(4-trifluoroacetamidobenzoyl)-HPI (obtainable from2-(4-aminobenzoyl)-HPI with trifluoroacetic anhydride/triethylamin) isheated with 34.2 g. of methyl iodide in 300 ml. of acetone almost to theboiling point; then, 13.4 g. of pulverized potassium hydroxide is addedthereto and the mixture refluxed for 5 minutes, whereupon the mixture isevaporated, combined with water, and stirred for 2 hours at 20°. Themixture is then extracted with chloroform, washed with water, andevaporated, yielding 2-(4-methylaminobenzoyl)-HPI, m.p. 220°.

If the methyl iodide is not removed prior to hydrolysis,2-(4-dimethylaminobenzoyl)-HPI is obtained, m.p. 225°-226°.

EXAMPLE 25

Analogously to Example 19, 2-(4-mercaptobenzoyl)-HPI is obtained from2-(4-methylmercaptobenzoyl)-HPI and boron tribromide.

Analogously, 2-(2-mercaptobenzoyl)-HPI and 2-(3-mercaptobenzoyl)-HPI canbe produced.

EXAMPLE 26

(a) At 0°, 1.15 g. of sodium borohydride is added in incrementalportions to 6.5 g. of 2-(4-oxocyclohexylcarbonyl)-HPI in 100 ml. ofethanol. The mixture is agitated for 12 hours at 20°, poured on ice, and2-(4-hydroxycyclohexylcarbonyl)-HPI is thus produced as a mixture ofisomers.

(b) Under nitrogen at -70°, 24 ml. of a 0.5-molar solution of potassiumtris(sec.-butyl)borohydride in THF is added to a solution of 3.25 g. of2-(4-oxocyclohexylcarbonyl)-HPI in 35 ml. of absolute THF. After 3hours, the mixture is combined with 35 ml. of water, allowed to warm upto 20°, and worked up with chloroform. Chromatographic purification onsilica gel with chloroform yieldscis-2-(4-hydroxycyclohexylcarbonyl)-HPI, m.p. 162°-163°.

EXAMPLE 27

6.5 g. of 2-(4-oxocyclohexylcarbonyl)-HPI in 100 ml. of methanol ishydrogenated in the presence of 2 g. of Raney nickel at 50° and under100 atmospheres to saturation. The reaction product is filtered off fromthe catalyst, the solvent is evaporated, and2-(4-hydroxycyclohexylcarbonyl)-HPI is thus obtained as a mixture ofisomers.

EXAMPLE 28

3.16 g. of 2-(4-oxocyclohexylcarbonyl)-HPI in 100 ml. of methanol,saturated at 10° with ammonia, is hydrogenated in the presence of 1 g.of Raney nickel at 70° and under 100 atmospheres for 10 hours. Thecatalyst is filtered off, the solvent is evaporated, and the residue isdissolved in ethanol. After adding HBr in ethanol and then combining themixture with ether, trans-2-(4-aminocyclohexylcarbonyl)-HPI hydrobromideis crystallized, m.p. 284°. From the filtrate, by adding NaOH,extraction with chloroform, and evaporation,cis-2-(4-aminocyclohexylcarbonyl)-HPI is obtained.

EXAMPLE 29

At room temperature and under 5 atmospheres, 3.1 g. of2-(4-oximinocyclohexylcarbonyl)-HPI (m.p. 194°; obtainable from2-(4-oxocyclohexylcarbonyl)-HPI and hydroxylamine) is hydrogenated in100 ml. of ethanol in the presence of 4 g. of Raney nickel untilsaturation. Evaporation yields 2-(4-aminocyclohexylcarbonyl)-HPI(mixture of isomers).

EXAMPLE 30

A solution of 5.5 g. of 2-isonicotinoyl-HPI and 6.3 g. of3-chloroperbenzoic acid (50%) is allowed to stand in methylene chlorideovernight at 20°. Then, ammonia is introduced to saturation, the mixtureis filtered and washed with methylene chloride. Evaporation of thefiltrate yields 2-isonicotinoyl-HPI-1'-N-oxide, m.p. 250° (fromethanol).

Analogously, 2-nicotinoyl-HPI-1'-N-oxide, m.p. 178°, is obtained from2-nicotinoyl-HPI.

Analogously, the corresponding N-oxides can be obtained from thedialkylamino compounds recited in Example 1, for example2-(4-dimethylaminobenzoyl)-HPI-N-oxide.

EXAMPLE 31

3.2 g. of 2-(4-dimethylaminobenzoyl)-HPI and 5 g. of methyl iodide isheated overnight in 600 ml. of acetonitrile to 75°; the solvent isevaporated, the thus-produced mixture is purified on silica gel (eluent:chloroform/methanol), thus obtaining the methoiodide of2-(4-dimethylaminobenzoyl)-HPI, m.p. 215°-216° (from ethanol).

EXAMPLE 32

2.1 g. of 1-aminocyclohexane-1-carboxylic acid is combined with 6.3 g.of trifluoroacetic anhydride. At 0°, 2 g. of HPI and 2.3 g. oftriethylamine in 20 ml. of methylene chloride are added thereto, and themixture is heated to 30°. After one hour, the reaction mixture is pouredinto water, the organic phase is separated, washed with sodium hydroxidesolution and water, dried, and evaporated, thus producing2-(1-aminocyclohexyl-1-carbonyl)-HPI, m.p. 146° (from benzene).

Analogously, the following compounds are obtained:

2-methylaminoacetyl-HPI

2-ethylaminoacetyl-HPI

2-(2-methylaminopropionyl)-HPI

2-(2-ethylaminopropionyl)-HPI

2-(3-methylaminopropionyl)-HPI

2-(3-ethylaminopropionyl)-HPI

2-(2-methylamino-n-butyryl)-HPI

2-(4-methylamino-n-butyryl)-HPI

2-(4-ethylamino-n-butyryl)-HPI

2-(2-methylamino-n-valeryl)-HPI

2-(5-methylamino-n-valeryl)-HPI

2-(1-methylaminocyclobutylcarbonyl)-HPI

2-(2-methylaminocyclobutylcarbonyl)-HPI

2-(3-methylaminocyclobutylcarbonyl)-HPI

2-(1-ethylaminocyclobutylcarbonyl)-HPI

2-(2-ethylaminocyclobutylcarbonyl)-HPI

2-(3-ethylaminocyclobutylcarbonyl)-HPI

2-(1-methylaminocyclopentylcarbonyl)-HPI

2-(2-methylaminocyclopentylcarbonyl)-HPI

2-(3-methylaminocyclopentylcarbonyl)-HPI

2-(1-ethylaminocyclopentylcarbonyl)-HPI

2-(2-ethylaminocyclopentylcarbonyl)-HPI

2-(3-ethylaminocyclopentylcarbonyl)-HPI

2-(2,4-diaminocyclohexylcarbonyl)-HPI

2-(3,4-diaminocyclohexylcarbonyl)-HPI

2-(3,5-diaminocyclohexylcarbonyl)-HPI

2-(1-methylaminocyclohexylcarbonyl)-HPI

2-(2-methylaminocyclohexylcarbonyl)-HPI

2-(3-methylaminocyclohexylcarbonyl)-HPI

2-(4-methylaminocyclohexylcarbonyl)-HPI

2-(1-ethylaminocyclohexylcarbonyl)-HPI

2-(2-ethylaminocyclohexylcarbonyl)-HPI

2-(3-ethylaminocyclohexylcarbonyl)-HPI

2-(4-ethylaminocyclohexylcarbonyl)-HPI

2-(2,4-bis-methylaminocyclohexylcarbonyl)-HPI

2-(3,4-bis-methylaminocyclohexylcarbonyl)-HPI

2-(3,5-bis-methylaminocyclohexylcarbonyl)-HPI

2-(2,4-bis-ethylaminocyclohexylcarbonyl)-HPI

2-(3,4-bis-ethylaminocyclohexylcarbonyl)-HPI

2-(3,5-bis-ethylaminocyclohexylcarbonyl)-HPI

2-(4-methylaminocycloheptylcarbonyl)-HPI

2-(4-ethylaminocycloheptylcarbonyl)-HPI

2-(2-methylaminobenzoyl)-HPI

2-(3-methylaminobenzoyl)-HPI

2-(4-methylaminobenzoyl)-HPI, m.p. 220°

2-(2-ethylaminobenzoyl)-HPI

2-(3-ethylaminobenzoyl)-HPI

2-(4-ethylaminobenzoyl)-HPI

2-(3,4-bis-methylaminobenzoyl)-HPI

2-(3,5-bis-methylaminobenzoyl)-HPI

2-(3,4-bis-ethylaminobenzoyl)-HPI

2-(3,5-bis-ethylaminobenzoyl)-HPI

2-(3-aminopicolinoyl)-HPI

2-(4-aminopicolinoyl)-HPI

2-(5-aminopicolinoyl)-HPI

2-(6-aminopicolinoyl)-HPI

2-(3-methylaminopicolinoyl)-HPI

2-(4-methylaminopicolinoyl)-HPI

2-(5-methylaminopicolinoyl)-HPI

2-(6-methylaminopicolinoyl)-HPI

2-(2-aminonicotinoyl)-HPI

2-(4-aminonicotinoyl)-HPI

2-(5-aminonicotinoyl)-HPI

2-(6-aminonicotinoyl)-HPI

2-(2-methylaminonicotinoyl)-HPI

2-(4-methylaminonicotinoyl)-HPI

2-(5-methylaminonicotinoyl)-HPI

2-(6-methylaminonicotinoyl)-HPI

2-(benzimidazolyl-2-carbonyl)-HPI

2-(pyrrolinyl-2-carbonyl)-HPI

2-(pyrrolidinyl-2-carbonyl)-HPI

2-(pyrrolidinyl-3-carbonyl)-HPI

2-(1,2,3,4-tetrahydropyridyl-1-carbonyl)-HPI

2-(1,2,3,4-tetrahydropyridyl-2-carbonyl)-HPI

2-(piperidyl-1-carbonyl)-HPI

2-(piperidyl-2-carbonyl)-HPI

2-(piperidyl-3-carbonyl)-HPI

2-(piperidyl-4-carbonyl)-HPI, monohydrate, m.p. 146°-147°

2-(1,2,3,4-tetrahydroquinolyl-3-carbonyl)-HPI

2-(1,2,3,4-tetrahydroquinolyl-4-carbonyl)-HPI

2-(1,2,3,4-tetranhydroisoquinolyl-1-carbonyl)-HPI

2-(1,2,3,4-tetrahydroisoquinolyl-3-carbonyl)-HPI

2-(1,2,3,4-tetrahydroisoquinolyl-4-carbonyl)-HPI.

If the organic phase is not washed with sodium hydroxide solution, thecorresponding trifluoroacetylamino compounds are also produced, forexample: 2-(1-trifluoroacetamidocyclohexylcarbonyl)-HPI.

EXAMPLE 33

4.04 g. of HPI and 1.5 g. of acetic acid are added to a suspension of4.2 g. of the Leuchs anhydride of4-aminotetrahydrothiopyran-4-carboxylic acid(1,3-dioxo-2-oxa-8-thiaspiro[4,5]decane; obtainable from this acid withphosgene) in 300 ml. of chloroform. The reaction mixture is refluxed for24 hours, cooled, filtered, the filtrate washed with dilute sodiumhydroxide solution and water, and evaporated, thus obtaining2-(4-aminotetrahydrothiopyran-4-carbonyl)-HPI, m.p. 157°-158° (fromethyl acetate/ether/petroleum ether).

EXAMPLE 34

In an autoclave, 3.26 g. of 2-(4-oxocyclohexylcarbonyl)-HPT, 0.2 ml. ofwater, and 3.2 g. of sulfur tetrafluoride are shaken in 50 ml. ofmethylene chloride for 24 hours at 30°. The mixture is then poured intodilute sodium carbonate solution, washed with water, dried over sodiumsulfate, and evaporated, thus producing2-(4,4-trifluorocyclohexylcarbonyl)-HPI.

EXAMPLE 35

3.4 g. of 2-(4-mercaptobenzoyl)-HPI is heated with 40 ml. of nitric acid(d=1.2) on a water bath. After the first vigorous reaction has dieddown, the mixture is evaporated, thus obtaining 2-(4-sulfobenzoyl)-HPI.

Analogously, 2-(2-sulfobenzoyl)-HPI and 2-(3-sulfobenzoyl)-HPI areproduced by oxidation of the corresponding mercapto compounds.

EXAMPLE 36

Analogously to Example 17, 8 g. of 2-(4-acetoxybenzoyl)-HPI issaponified in the presence of 10% sodium hydroxide solution, thusobtaining 2-(4-hydroxybenzoyl)-HPI, m.p. 243°-245°.

In an analogous manner, the following final products are produced bysaponification of the corresponding acetates:

2-(2-hydroxyacetyl)-HPI

2-(2-hydroxycyclopropylcarbonyl)-HPI

2-(1-hydroxycyclobutylcarbonyl)-HPI

2-(2-hydroxycyclobutylcarbonyl)-HPI

2-(3-hydroxycyclobutylcarbonyl)-HPI

2-(1-hydroxycyclopentylcarbonyl)-HPI

2-(2-hydroxycyclopentylcarbonyl)-HPI

2-(3-hydroxycyclopentylcarbonyl)-HPI

2-(1-hydroxycyclohexylcarbonyl)-HPI

2-(2-hydroxycyclohexylcarbonyl)-HPI

2-(3-hydroxycyclohexylcarbonyl)-HPI

2-(4-hydroxycyclohexylcarbonyl)-HPI

(+)-2-(4-hydroxycyclohexylcarbonyl)-HPI

(-)-2-(4-hydroxycyclohexylcarbonyl)-HPI

2-(2,4-dihydroxycyclohexylcarbonyl)-HPI

2-(3,4-cis-dihydroxycyclohexylcarbonyl)-HPI, hydrate, m.p. 100°-102°

2-(3,5-dihydroxycyclohexylcarbonyl)-HPI

2-(3,4,5-trihydroxycyclohexylcarbonyl)-HPI.

EXAMPLE 37

Analogously to Example 1, 2-(4-benzyloxycarbonylaminobenzoyl)-HPI isproduced from HPI and 4-(benzyloxycarbonylamino)-benzoyl chloride.

The following final products are obtained analogously with thecorresponding acid halogenides:

2-(4-methoxyacetamidocyclohexylcarbonyl)-HPI

2-(4-tert.-butoxycarbonylaminocyclohexylcarbonyl)-HPI

2-(4-benzyloxycarbonylaminocyclohexylcarbonyl)-HPI

2-[4-(3,5-dimethoxybenzyl-oxycarbonyl)-aminocyclohexylcarbonyl]-HPI

2-(2-methoxyacetamidobenzoyl)-HPI

2-(2-tert.-butoxycarbonylaminobenzoyl)-HPI

2-(2-benzyloxycarbonylaminobenzoyl)-HPI

2-[2-(3,5-dimethoxybenzyl-oxycarbonyl)-aminobenzoyl]-HPI

2-(3-methoxyacetamidobenzoyl)-HPI

2-(3-tert.-butoxycarbonylaminobenzoyl)-HPI

2-(3-benzyloxycarbonylaminobenzoyl)-HPI

2-[3-(3,5-dimethoxybenzyl-oxycarbonyl)-aminobenzoyl]-HPI

2-(4-methoxyacetamidobenzoyl)-HPI, m.p. 172°

2-(4-tert.-butoxycarbonylaminobenzoyl)-HPI

2-[4-(3,5-dimethoxybenzyl-oxycarbonyl)-aminobenzoyl]-HPI

2-(1-tert.-butoxycarbonylpiperidyl-3-carbonyl)-HPI

2-(1-benzyloxycarbonylpiperidyl-3-carbonyl)-HPI

2-[1-(3,5-dimethoxybenzyl-oxycarbonyl)-piperidyl-3-carbonyl]-HPI

2-(1-benzyloxycarbonylpiperidyl-4-carbonyl)-HPI.

EXAMPLE 38

4.5 g. of 2-(1-benzyloxycarbonylpiperidyl-3-carbonyl)-HPI ishydrogenated in 100 ml. of 80% aqueous dioxane and 1 ml. of acetic acidon 300 mg. of palladium; the catalyst is filtered off, evaporated, theresidue taken up in chloroform, washed with soda solution and water,evaporated, and the product is 2-(piperidyl-3-carbonyl)-HPI.

Analogously, the following compounds are produced by hydrogenolysis ofthe corresponding benzyloxycarbonylamino acyl derivatives:

trans-2-(4-aminocyclohexylcarbonyl)-HPI, hydrobromide, m.p. 284°

2-(2-aminobenzoyl)-HPI, hydrobromide, m.p. 279°-280°

2-(3-aminobenzoyl)-HPI, m.p. 161°-162°

2-(4-aminobenzoyl)-HPI, m.p. 212°-213°

2-(piperidyl-4-carbonyl)-HPI, monohydrate, m.p. 146°-147°.

EXAMPLE 39

A solution of 4.3 g. of 2-(1-tert.-butoxycarbonylpiperidyl-3-carbonyl)HPI in 80 ml. of 98% formic acid is allowed to stand for 5 hours at 20°.The mixture is then evaporated, the residue taken up in chloroform,washed with soda solution and water, and evaporated, thus obtaining2-(piperidyl-3-carbonyl)-HPI.

EXAMPLE 40

A solution of 5.1 g. of2-[1-(3,5-dimethoxybenzyloxycarbonyl)-piperidyl-3-carbonyl]-HPI in 100ml. of 80% aqueous dioxane is irradiated for 2 hours with ahigh-pressure mercury lamp. The mixture is combined with hydrochloricacid, washed with ether, made alkaline with sodium hydroxide solution,extracted with chloroform, and evaporated, thus producing2-(piperidyl-3-carbonyl)-HPI.

EXAMPLE 41

6.4 g. of 2-(4-aminobenzoyl)-HPI, 2.7 g. of salicyclic aldehyde, and 100mg. of p-toluenesulfonic acid chloride are refluxed in 150 ml. oftoluene for 12 hours; the thus-liberated water is removed. The mixtureis evaporated and triturated with ether, thus obtaining2-(4-o-hydroxybenzylideneaminobenzoyl)-HPI, m.p. 196°-197° (frombenzene/petroleum ether).

Analogously, 2-(4-benzylideneaminobenzoyl)-HPI is obtained withbenzaldehyde.

EXAMPLE 42

3 g. of 2-(4-benzylideneaminobenzoyl)-HPI is hydrogenated in 50 ml. ofmethanol on 1 g. of platinum for 3 hours at 20° and under normalpressure. After the catalyst has been filtered off and the mixtureevaporated, 2-(4-benzylaminobenzoyl)-HPI is obtained, m.p. 204°-205°.

Analogously, the following compounds are produced from the correspondingSchiff bases by hydrogenation:

2-(3-benzylaminocyclopentylcarbonyl)-HPI

2-(4-benzylaminocyclohexylcarbonyl)-HPI

2-(3-benzylaminobenzoyl)-HPI

2-[3-(2-hydroxybenzyl)-aminocyclopentylcarbonyl]-HPI

2-[4-(2-hydroxybenzyl)-aminocyclohexylcarbonyl]-HPI

2-[3-(2-hydroxybenzyl)-aminobenzoyl]-HPI

2-[4-(2-hydroxybenzyl)-aminobenzoyl]-HPI, m.p. 201°-202°

2-[3-(2-hydroxy-3-methoxybenzyl)-aminocyclopentylcarbonyl]-HPI

2-[4-(2-hydroxy-3-methoxybenzyl)-aminocyclohexylcarbonyl]-HPI

2-[3-(2-hydroxy-3-methoxybenzyl)-aminobenzoyl]-HPI

2-[4-(2-hydroxy-3-methoxybenzyl)-aminobenzoyl]-HPI

2-(3-carboxymethylaminocyclopentylcarbonyl)-HPI

2-(4-carboxymethylaminocyclohexylcarbonyl)-HPI

2-(3-carboxymethylaminobenzoyl)-HPI

2-(4-carboxymethylaminobenzoyl)-HPI.

Instead of using platinum during the hydrogenation, the reaction canalso be conducted with Raney nickel; dioxane is used as the solvent inthis case, and the hydrogenation is effected at 45° and 1-5 atmospheres.

EXAMPLE 43

Analogously to Example 38, 2-(4-aminobenzoyl)-HPI, m.p. 212°-213°, isobtained from 2-(4-benzylideneaminobenzoyl)-HPI by hydrogenation onpalladium.

EXAMPLE 44

At 5°-10°, a diazonium salt solution prepared from 3.21 g. of2-(4-aminobenzoyl)-HPI, 5 ml. of 6 N hydrochloric acid, 0.7 g. of sodiumnitrite, and 4 ml. of water is poured into a solution of 1.38 g. ofsalicyclic acid in 15 ml. of 2 N sodium hydroxide solution. Care istaken that the solution remains alkaline. After one-half hour, thethus-obtained product is precipitated with hydrochloric acid, filteredoff, washed with water and a small quantity of ethanol, and dried,yielding 2-[4-(3-carboxy-4-hydroxyphenylazo)-benzoyl]-HPI as anorange-yellow powder; m.p. 241°-244°.

Analogously, the following final products are obtained with anisole anddimethylaniline:

2-(4-p-methoxyphenylazobenzoyl)-HPI

2-(4-p-dimethylaminophenylazobenzoyl)-HPI.

EXAMPLE 45

300 ml. of a 3.7 N solution of sodium bisulfite is heated with 49 g. ofcinnamic aldehyde for one-half hour to 90°. To this mixture is added111.7 g. of 2-(4-aminobenzoyl)-HPI in 1 l. of dioxane, and the mixtureis heated for 12 hours to 90°. After cooling, an extraction is carriedout with chloroform; the aqueous phase is concentrated, and the productis precipitated by adding ethanol, thus obtaining the disodium salt of2-[4-(1,3-disulfo-3-phenylpropylamino)-benzoyl]-HPI; m.p. 221°-222°(decomposition).

EXAMPLE 46

Analogously to Example 24, 2-(4-allylaminobenzoyl)-HPI is produced from2-(4-aminobenzoyl)-HPI and allyl iodide.

The following compounds are analogously obtained:

2-(3-allylaminocyclopentylcarbonyl)-HPI

2-(4-allylaminocyclohexylcarbonyl)-HPI

2-(3-allylaminobenzoyl)-HPI.

EXAMPLE 47

Analogously to Example 5, the following final products are obtained fromthe corresponding amino compounds with succinic anhydride, maleicanhydride, and phthalic anhydride, respectively:

2-(4-succinylaminobenzoyl)-HPI

2-(4-maleinoylaminobenzoyl)-HPI

2-(4-phthaloylaminobenzoyl)-HPI

2-(1-succinylpiperidyl-4-carbonyl)-HPI

2-(1-maleinoylpiperidyl-4-carbonyl)-HPI

2-(1-phthaloylpiperidyl-4-carbonyl)-HPI.

EXAMPLE 48

4.8 g. of 2-(3-cyclohexenyl-1-carbonyl)-HPI and 4 g. of osmium tetroxideare agitated overnight in 60 ml. of pyridine at 20°; then, a solution of7 g. of sodium bisulfite in 110 ml. of water and 85 ml. of pyridine isadded thereto and the mixture stirred for 30 minutes, whereupon it isextracted with methylene chloride. Drying and evaporation yield2-(3,4-cis-dihydroxycyclohexyl-1-carbonyl)-HPI, hydrate, m.p. 100°-102°.

EXAMPLE 49

3.1 g. of 2-(3-cyclohexenyl-1-carbonyl)-HPI is hydrogenated on 300 mg.of platinum oxide in 100 ml. of methanol at 20° and under normalpressure until the reaction has ceased; the mixture is then filtered andevaporated, thus obtaining 2-cyclohexylcarbonyl-HPI, m.p. 136°-138°.

EXAMPLE 50

A solution of 3.3 g. of 2-(tetrahydrothiopyran-4-carbonyl)-HPI and 1.05ml. of 30% aqueous hydrogen peroxide is allowed to stand overnight at20° in 20 ml. of acetic acid; then, the mixture is evaporated and workedup with chloroform and water, yielding2-(tetrahydrothiopyran-4-carbonyl)-HPI-S-oxide as a mixture of isomers,m.p. 175°-180°.

EXAMPLE 51

3.3 g. of 2-(tetrahydrothiopyran-4-carbonyl)-HPI and 2.5 ml. of 30%aqueous hydrogen peroxide are heated in 25 ml. of acetic acid for 2hours to 60°; the mixture is then evaporated and worked up withchloroform and water, thus obtaining2-(tetrahydrothiopyran-4-carbonyl)-HPI-S,S-dioxide, m.p. 253°-255° (fromethanol).

EXAMPLE 52

Under nitrogen, 35 ml. of a 0.5-molar solution of potassiumtri-sec.-butyl borohydride in THF is added gradually at -70° to asolution of 4.9 g. of 2-(4-oxocyclohexylcarbonyl)-HPI in 50 ml. ofabsolute THF. After 3 hours, the mixture is mixed with 50 ml. of water,allowed to come to room temperature, acidified with HCl, and extractedwith chloroform. The chloroform extract is purified by chromatography(silica gel/chloroform), thus obtaining purecis-2-(4-hydroxycyclohexylcarbonyl)-HPI, m.p. 162°-163° (fromisopropanol/diethyl ether).

The effective agents of Formula 1 can be processed to pharmaceuticalpreparations according to methods known from the literature, asdemonstrated by the following examples:

EXAMPLE A

Tablets to Combat Cestodes (Adult Form)

(a) Tablets containing 500 mg. of 2-cyclohexylcarbonyl-HPI as the activeingredient are produced by processing a powder mixture of 5 kg. of2-cyclohexylcarbonyl-HPI, 3 kg. of lactose, 1.8 kg. of corn starch, and0.2 kg. of magnesium stearate.

(b) The same mixture can be utilized for the production of tabletscontaining 50, 250 and 1,000 mg. of 2-cyclohexylcarbonyl-HPI.

The tablets containing 250 and 500 mg. of 2-cyclohexylcarbonyl-HPI arepreferably utilized for purposes of human medicine; all above-describedtablets can be used for veterinary purposes.

EXAMPLE B

Tablets to Combat Preferably Cestode Cysticerci and/or Schistosoma

(a) Effervescent Tablet

Each tablet contains:

    ______________________________________                                        2-Cyclohexylcarbonyl-PHI                                                                         1,000       mg.                                            Citric acid        800         mg.                                            Sodium carbonate   900         mg.                                            Saccharin          5           mg.                                            Saccharose         ad 4,000    mg.                                            ______________________________________                                    

(b) Chewable Sugar Tablet

Each tablet contains:

    ______________________________________                                        2-Cyclohexylcarbonyl-HPI                                                                           2,000 mg.                                                Cellulose            80 mg.                                                   Carboxymethylcellulose                                                        sodium salt          40 mg.                                                   Coloring agent and flavor-                                                    ing substances       as desired                                               Saccharose           ad 4,000 mg.                                             ______________________________________                                    

EXAMPLE C

Dragees to Combat Cestodes in Human Medicine

The dragee core contains the following ingredients:

    ______________________________________                                        2-Cyclohexylcarbonyl-HPI                                                                              250 mg.                                               Lactose                 150 mg.                                               Corn starch              90 mg.                                               Magnesium stearate       10 mg.                                               ______________________________________                                    

The dragee coating is composed of: talc, saccharose, titanium dioxide,calcium carbonate, polyvinylpyrrolidone, methylcellulose, glycerin,magnesium oxide, lacquer.

This formulation can also be used for dragees containing 500 mg. of2-cyclohexylcarbonyl-HPI as the active agent.

EXAMPLE D

Elixir to Combat Cestodes (Human Medicine)

The elixir is prepared by making a suspension of the following:

    ______________________________________                                        2-Cyclohexylcarbonyl-HPI                                                                            3.5       kg.                                           Distilled water       2         1.                                            Buffer                0.1       1.                                            Glycerin              3         kg.                                           Sorbitol              3         kg.                                           Saccharose            53        kg.                                           Mixture of 60% methyl p-                                                      hydroxybenzoate and 40%                                                       propyl p-hydroxybenzoate                                                                            0.1       kg.                                           Ethanol               12. 1.                                                  ______________________________________                                    

The mixture is combined with coloring and flavoring agents and filled upto a volume of 100 l. with distilled water.

EXAMPLE E

Capsules for Combating Cestodes and Schistosoma for Human and VeterinaryMedicine

Capsules of a corresponding size are filled with a mixture of:

    ______________________________________                                        2-Cyclohexylcarbonyl-HPI                                                                             5,000 mg.                                              Talc                   250 mg.                                                Magnesium stearate     150 mg.                                                ______________________________________                                    

Correspondingly, capsules are produced containing 1,000 mg. and 10,000mg. of 2-cyclohexylcarbonyl-HPI.

EXAMPLE F

Injection Fluid for Purposes of Human and Veterinary Medicine

For subcutaneous administration in an oily or aqueous suspension, 15mg.-ampoules are filled with a solution of 500 mg. of2-cyclohexylcarbonyl-HPI in 6 ml. of water and 4 ml. of propyleneglycol, with the addition of a solubilizer. The ampoules are sterilizedby heat or mixed with a preservative.

Correspondingly, ampoules are produced containing 100 mg. of2-cyclohexylcarbonyl-HPI (for small animals) and 1,000 mg. of2-cyclohexylcarbonyl-HPI (for large animals).

EXAMPLE G

Pellets

A pulverulent mixture is prepared from equal parts by weight of2-cyclohexylcarbonyl-HPI and lactose; this mixture is converted togetherwith carboxymethylcellulose sodium salt in the usual manner into auniformly granulated material having an average particle diameter of 1.5mm.

EXAMPLE H

Premix for Purposes of Veterinary Medicine, Suitable for Mixing with aFeed Material as the Vehicle to Obtain a Medical Animal Food

(a) 25% Premix (preferably for larger animals):

25 kg. of 2-cyclohexylcarbonyl-HPI is mixed with 75 kg. of fine bran(wheat middlings) and/or lactose.

(b) 5% Premix (preferably for smaller animals):

5 kg. of 2-cyclohexylcarbonyl-HPI are processed analogously to (a).

(c) Example for the use of a premix produced according to (a) forcombating Moniezia genera in the cattle intestine.

To obtain a suitable medical feed, 1 kg. of the premix producedaccording to (a) is combined with 9 kg. of a conventional feedconcentrate. To combat Moniezia infestation, 400 g. of this medicalfeed, containing 10,000 mg. of 2-cyclohexylcarbonyl-HPI, is administeredto adult cattle, per head.

Analogously to Examples A-H, it is also possible to process, in place of2-cyclohexylcarbonyl-HPI, the other active agents of Formula 1 or thephysiologically acceptable salts thereof to obtain pharmaceuticalpreparations.

The preceding examples can be repeated with similar success bysubstituting the generically and specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound of the formula ##STR5## wherein R isphenyl mono-substituted in the o-position by fluorine or in the m- orp-position by fluorine, chlorine, nitro, hydroxy, amino, formylamino,acetylamino, pentanoylamino, hexanoylamino, octanoylamino, oleoylamino,methoxyacetylamino, methylamino, dimethylamino or allylamino, or aphysiologically acceptable acid addition salt thereof.
 2. A compound ofclaim 1,2-(2-fluorobenzoyl)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.3. A compound of claim 1,2-(3-fluorobenzoyl)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.4. A compound of claim 1,2-(4-fluorobenzoyl)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.5. A compound of claim 1,2-(3-aminobenzoyl)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.6. A compound of claim 1,2-(4-aminobenzoyl)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.7. A compound of claim 1,2-(3-formamidobenzoyl)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.8. A compound of claim 1,2-(4-formamidobenzoyl)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.9. A compound of claim 1,2-(4-nitrobenzoyl)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazinl[2,1-a]isoquinoline.10. A compound of claim 1,2-(4-methylaminobenzoyl)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.11. A compound of claim 1,2-(4-dimethylaminobenzoyl)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.12. A compound of claim 1,2-(3-acetamidobenzoyl)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.13. A compound of claim 1,2-(4-acetamidobenzoyl)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.14. A compound of claim 1,2-(3-methoxyacetamidobenzoyl)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.15. A compound of claim 1,2-(4-methoxyacetamidobenzoyl)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.